KR102268448B1 - Toll-like receptor modulator compounds - Google Patents

Abstract

The present application relates to Toll-like receptor modulators (eg TLR8) compounds of formula (I) and pharmaceutical compositions containing them. The compounds are useful for the treatment of hyperproliferative diseases such as cancer or viral infections such as hepatitis B and HIV.

Description

Toll-like receptor modulator compounds

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Serial No. 62/383,162, filed September 2, 2016, the disclosure of which is incorporated by reference in its entirety.

technical field

The present application relates generally, inter alia, to Toll-like receptor modulator compounds and pharmaceutical compositions that modulate a Toll-like receptor (eg, TLR8), and methods of making and using the same.

background

The Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR8) is predominantly expressed by myeloid immune cells, and activation of this receptor stimulates a wide range of immunological responses. Agonists of TLR8 activate bone marrow dendritic cells, monocytes, monocyte-derived dendritic cells and Kupffer cells, which in turn activate pro-inflammatory cytokines and chemokines such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor leads to the production of necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). Such agonists also promote increased expression of co-stimulatory molecules such as CD8 ⁺ cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors.

Collectively, the activation of these innate and adaptive immune responses induces immune responses and is associated with a variety of factors involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency. provides a therapeutic benefit in the condition. For example, with respect to hepatitis B, activation of TLR8 on professional antigen presenting cells (pAPCs) and other intrahepatic immune cells is associated with the induction of IL-12 and pro-inflammatory cytokines, which are HBV-specific T cell responses. It is expected to enhance the liver, activate intrahepatic NK cells, and drive the reconstitution of antiviral immunity. See, for example, Wille-Reece, U. et al. J Exp Med 203, 1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J. et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., J Biol Chem 288, 31715-31727 (2013).

Given their potential to treat a variety of diseases, there remains a need for novel modulators of Toll-like receptors, such as TLR8. Potent and selective modulators of TLR8 with reduced potential for off-target burden are particularly desirable.

summary

The present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.

here,

R ¹ is —H, C _1-4 alkyl, or C _1-4 haloalkyl;

R ² is C _1-6 alkyl or C _1-6 haloalkyl;

R ³ _{is C 1-4} alkoxy optionally substituted with 1 R ^{X ;}

each R ^X is independently —OR ^Y , 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} or 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

R ^Y is C _1-4 alkyl, C _1-4 haloalkyl, or 5-10 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} ;

Q is N, CH, or CR ⁴ ;

or R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein

C _5-6 cycloalkyl and phenyl are each independently optionally substituted ^{with 1 to 3 R 5 ;}

each R ⁵ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with ^{1-3 R Z} , C _1-4 haloalkyl, C _1-4 alkoxy, —C (O)OH, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), - C(O)N(C _1-4 alkyl) ₂ , —N(H)C(O)C _1-4 alkyl, —S(O) ₂ C _1-4 alkyl, or optionally with ^{1-3 R Z} 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from substituted oxygen, nitrogen, and sulfur;

5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;}

each R ⁶ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with 1 phenyl optionally substituted with ^{1-3 R Z ;} C _1-4 haloalkyl, C _1-4 alkoxy, —S(O) ₂ C _1-4 alkyl; 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} or 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

5-6 membered heterocyclyl is optionally substituted with ^{1-3 R 7 ;}

R ⁷ is halogen, —OH, C _1-4 alkyl, C _1-4 alkoxy, or —C(O)R ⁸ ;

each R ⁸ _{is independently C 1-4} alkyl optionally substituted with —CN or —NH _{2 ;} C _1-4 haloalkyl; C _5-6 cycloalkyl, 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} or 5-10 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

each R ^Z is independently —NH ₂ , C _1-4 alkyl, halogen, —CN, —OC _1-4 alkyl, C _1-4 haloalkyl, or —C(O)NH ₂ ;

이 아니다.with the proviso that formula I is

this is not

In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents.

In certain embodiments, a method of modulating TLR8 is provided comprising administering to an individual (eg, a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (eg, a human) in need of treatment or prevention of a disease or condition responsive to modulation of TLR8. Methods of treating or preventing a disease or condition responsive to modulation of TLR8 are provided, comprising. In certain embodiments, a method of treating or preventing a disease or condition responsive to modulation of TLR8 comprises administering one or more additional therapeutic agents.

In certain embodiments, treating a viral infection comprising administering to an individual (eg, a human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof Or a method of preventing is provided.

In certain embodiments, B comprising administering to an individual (eg, a human) in need of treatment or prevention of hepatitis B virus infection, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof Methods for treating or preventing hepatitis virus infection are provided. In certain embodiments, the method of treating or preventing hepatitis B virus infection comprises administering one or more additional therapeutic agents. In certain embodiments, the individual is a human infected with hepatitis B.

In certain embodiments, treating HIV infection comprising administering to an individual (eg, a human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof Or a method of preventing is provided. In certain embodiments, the method of treating or preventing HIV infection comprises administering one or more additional therapeutic agents. In certain embodiments, the individual is a human infected with HIV (eg, HIV-1).

In certain embodiments, comprising administering to an individual (eg, a human) in need of treatment of a hyperproliferative disease (eg, cancer) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof A method of treating a hyperproliferative disease (eg, cancer) is provided. In certain embodiments, a method of treating a hyperproliferative disease (eg, cancer) comprises administering one or more additional therapeutic agents. In certain embodiments, the individual is a human.

In certain embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In certain embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition responsive to modulation of TLR8. In certain embodiments, the disease or condition is a viral infection.

In certain embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing hepatitis B.

In certain embodiments, there is provided the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease or condition responsive to modulation of TLR8.

In certain embodiments, there is provided the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing hepatitis B.

Also provided is a kit comprising the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. Also provided is an article of manufacture comprising a unit dose of the compound or a pharmaceutically acceptable salt thereof. Also provided are methods of making the compounds of the present disclosure.

details

It is understood that the following description is to be regarded as an illustration of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

I. Definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash before or after a chemical group is expedient to indicate the point of attachment to the parent moiety; A chemical group may be indicated with or without one or more dashes without losing its ordinary meaning. A prefix such as "C _uv " or (C _u -C _v ) indicates that the following group has u to v carbon atoms, where u and v are integers. For example, “C _1-6 alkyl” indicates that the alkyl group has 1 to 6 carbon atoms.

"Alkyl" is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group may have 1 to 10 carbon atoms (ie (C _1-10 )alkyl) or 1 to 8 carbon atoms (ie (C _1-8 )alkyl) or 1 to 6 carbon atoms (ie. , (C _1-6 alkyl) or 1 to 4 carbon atoms (ie (C _1-4 )alkyl) Examples of alkyl groups are methyl (Me, —CH ₃ ), ethyl (Et, — CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1- Butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2- Butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ) , 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2- methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl- 2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH) ₃ )C(CH ₃ ) ₃ , and octyl (—(CH ₂ ) ₇ CH ₃ ).

As used herein, the term “halo” or “halogen” refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

The term “haloalkyl,” as used herein, refers to an alkyl, as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different. For example, C _1-8 haloalkyl is C _1-8 alkyl in which at least one of the hydrogen atoms of the C _1-8 alkyl has been replaced by a halo substituent. Examples of haloalkyl groups include fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl, It is not limited thereto.

As used herein, the term “aryl” refers to a single all-carboaromatic ring or a multiple condensed all-carbocyclic ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes the phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having from about 9 to 20 carbon atoms, wherein at least one ring is aromatic and the other The ring may or may not be aromatic (ie carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (eg, 1, 2 or 3) oxo groups in any carbocycle portion of the multiple condensed ring system. The rings of a multiple condensed ring system may be linked to each other via fusion, spiro and cross-linking where valency requirements permit. Also, when a particular atom-range membered aryl (eg, 6-10 membered aryl) is recited, it is to be understood that the atomic range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

As used herein, the term “heteroaryl” refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "Heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes single aromatic rings of about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Sulfur and nitrogen atoms may also be present in oxidized form, with the proviso that the ring will be aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. Also, "heteroaryl" includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings), wherein a heteroaryl group as defined above is a heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (eg, to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (eg to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl) condensed with one or more rings selected from, e.g., 5,6,7,8-tetrahydroquinolyl) and aryl (e.g., to form indazolyl) to form a multiple condensed ring system . Thus, a heteroaryl (single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple fused ring systems may be optionally substituted with one or more (eg, 1, 2, 3 or 4) oxo groups in the carbocycle or heterocycle portion of the fused ring. The rings of a multiple condensed ring system may be linked to each other via fusion, spiro and cross-linking where valency requirements permit. It should be understood that the individual rings of a multiple condensed ring system may be linked in any order with respect to each other. It should be understood that the point of attachment to a heteroaryl or heteroaryl multiple condensed ring system may be any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (eg, nitrogen). do. Also, where a particular atom-range membered heteroaryl (eg, 5-10 membered heteroaryl) is recited, the atomic range is to the total ring atoms of the heteroaryl, and is understood to include carbon atoms and heteroatoms. should be For example, a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls are pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl , thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimida zolyl, thianaphtenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b; 4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “cycloalkyl” refers to a single saturated or moiety having 3 to 20 cyclic carbon atoms (ie C _3-20 cycloalkyl), for example 3 to 12 cyclic atoms, eg 3 to 10 cyclic atoms. Unsaturation refers to all carbon rings. The term "cycloalkyl" also includes polycondensed, saturated and partially unsaturated all carbocyclic ring systems (eg, ring systems comprising 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl is a multicyclic carbocycle, such as a bicyclic carbocycle (eg, about 6 to 12 cyclic carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane bicyclic carbocycles) and polycyclic carbocycles (eg, tricyclic and tetracyclic carbocycles having up to about 20 cyclic carbon atoms). The rings of a multiple condensed ring system may be linked to each other via fusion, spiro and cross-linking where valency requirements permit. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1 -cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

As used herein, the term “heterocyclyl” or “heterocycle” refers to a single saturated or partially unsaturated non- having at least one heteroatom in the ring (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur). refers to an aromatic ring or a non-aromatic multiple ring system. Unless otherwise specified, a heterocyclyl group has from 5 to about 20 ring atoms, for example from 3 to 12 ring atoms, for example from 5 to 10 ring atoms. Thus, the term refers to a single saturated or partially unsaturated ring having from about 1 to 6 cyclic carbon atoms in the ring and from about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (e.g., 3, 4 , 5, 6 or 7-membered ring). The rings of a multiple condensed ring system may be linked to each other via fusion, spiro and cross-linking where valency requirements permit. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.

As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired outcomes include, but are not limited to, alleviation of symptoms and/or reduction of the severity of symptoms and/or prevention of exacerbation of symptoms associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (eg, reducing one or more symptoms resulting from the disease or condition) , and/or reducing the severity of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (eg, stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or survival to prolong.

“Compounds of the present disclosure” include compounds disclosed herein, for example, compounds of the present disclosure include compounds of Formulas (I), (II), (III), and compounds listed in Table 1 . Compounds of the present disclosure also include compounds of Formulas (I), (II), and (III), the compounds of Examples 1-14, and the compounds listed in Table 1. The compounds of the present disclosure also include the compounds of Examples 1-14.

As used herein, “delaying” the development of a disease or condition means retarding, impeding, slowing, arresting, stabilizing and/or delaying the development of the disease or condition. This delay can be of varying lengths of time depending on the condition being treated and/or the individual's medical history. As will be apparent to one of ordinary skill in the art, a sufficient or significant delay can encompass prevention of in fact not developing the disease or condition in an individual. For example, a method of “delaying” the development of AIDS may include reducing the likelihood of developing a disease within a given time frame and/or reducing the severity of the disease within a given time frame as compared to not using the method. way. Such comparisons may be based on clinical studies using a statistically significant number of subjects. For example, the development of AIDS is determined by known methods, such ^{as determining an individual's HIV +} status and an individual's T-cell count or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, sore throat, , swollen lymph nodes in the armpit or groin, or an opportunistic condition known to be associated with AIDS (e.g., a condition that does not normally exist in individuals with a functional immune system but occurs in AIDS patients). can Development may also refer to disease progression that may be initially undetectable and includes development, recurrence and onset.

As used herein, “prevention” or “preventing” refers to therapy that protects against the onset of a disease or disorder such that the clinical symptoms of the disease do not develop. Thus, “prevention” refers to administering therapy (eg, administering a therapeutic agent) to a subject before signs of disease are detectable in the subject (eg, a detectable infectious agent in the subject (eg, administering a therapeutic substance to a subject in the absence of a virus). A subject may be an individual at risk of developing a disease or disorder, such as an individual having one or more risk factors known to be associated with the development or onset of a disease or disorder. Thus, in certain embodiments, the term “preventing HBV infection” refers to administration of an anti-HBV therapeutic agent to a subject who does not have a detectable HBV infection. It is understood that a subject for anti-HBV prophylactic therapy may be an individual at risk of contracting the HBV virus. Thus, in certain embodiments, the term “preventing HIV infection” refers to administration of an anti-HIV therapeutic agent to a subject who does not have a detectable HIV infection. It is understood that a subject for anti-HIV prophylactic therapy may be an individual at risk of contracting the HIV virus.

As used herein, an "at risk" individual is an individual at risk of developing the condition being treated. An individual “at risk” may or may not have a detectable disease or condition, and may or may not exhibit a detectable disease prior to the treatment methods described herein. "At risk" indicates that an individual has one or more so-called risk factors that correlate with the development of a disease or condition and are measurable parameters known in the art. Individuals with one or more of these risk factors are more likely to develop the disease or condition than individuals without these risk factor(s). For example, an individual at risk for AIDS has HIV.

As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, such as an amount of a compound sufficient to effect such treatment for a disease when administered to a subject for treating a disease. refers to An effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc. of the subject being treated. An effective amount can include a range of amounts. As is understood in the art, an effective amount may be one or more doses, ie, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be provided in an effective amount when a desired or beneficial result can be achieved or achieved in combination with one or more other agents. Suitable doses of any co-administered compound may optionally be reduced due to the combined action (eg, additive or synergistic effect) of the compounds.

As used herein, an “agonist” is a substance that stimulates its binding partner, typically a receptor. A stimulus is compared to a factor or substance that is defined in the context of a particular assay, or that is accepted as an "agonist" or "antagonist" of a particular binding partner under substantially similar circumstances, as would be appreciated by those of ordinary skill in the art. It may become apparent from the literature from the discussion herein. Stimulation may be defined in terms of an increase in a particular effect or function induced by the interaction of an agonist or partial agonist with a binding partner, and may include an allosteric effect.

As used herein, an “antagonist” is a substance that inhibits its binding partner, typically a receptor. Inhibition is compared to a factor or substance that is defined in the context of a particular assay, or that is accepted as an "agonist" or "antagonist" of a particular binding partner under substantially similar circumstances, as would be appreciated by one of ordinary skill in the art. It may become apparent from the literature from the discussion herein. Inhibition may be defined with respect to a decrease in a particular effect or function induced by the interaction of an antagonist with a binding partner, and may include an allosteric effect.

As used herein, a "partial agonist" or "partial antagonist" is a substance that provides to its binding partner a level of stimulation or inhibition, respectively, that is insufficient or incomplete agonism or antagonism, respectively. It will be appreciated that stimulation, and thus inhibition, is uniquely defined for any substance or category of substances that will be defined as an agonist, antagonist or partial agonist.

As used herein, “endogenous activity” or “potency” relates to some measure of the biological effectiveness of a binding partner complex. With respect to receptor pharmacology, the context in which endogenous activity or potency is to be defined will depend on the context of the binding partner (eg, receptor/ligand) complex and consideration of the activity associated with a particular biological outcome. For example, in some situations, endogenous activity may depend on the particular second messenger system involved. It will be apparent to one of ordinary skill in the art when certain assessments are appropriate in this context and how they may relate to the context of the present disclosure.

"Pharmaceutically acceptable excipient" means, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock. , flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizing agents, isotonicity agents, solvents or emulsifying agents.

As used herein, modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism or inverse agonism of the receptor.

The nomenclature used herein to name a subject compound is exemplified in the Examples and elsewhere herein.

As used herein, “co-administration” refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, eg, administration of the one or more additional therapeutic agents in seconds, minutes. or administration of a compound disclosed herein within hours. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents after a period of hours (eg, 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a period of hours (eg, 1-12 hours) after a unit dose of a compound of the present disclosure is administered.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, dosage forms and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

The compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that retain the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda. Id, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate , fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lac tate, γ-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington: The Science and Practice of Pharmacy, 21 ^st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein also include suitable bases such as alkali metals (eg sodium, potassium), alkaline earth metals (eg magnesium), ammonium and NX ₄ ⁺ (where X is C ₁ -C ₄ alkyl). Also included are base addition salts, such as sodium or potassium salts.

Also provided is a compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced with a deuterium atom or D, wherein n is an intramolecular hydrogen atom is the number of As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and thus may be useful for increasing the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof upon administration to a mammal. See, eg, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984)]. Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, respectively. , ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of formula (I) are generally prepared by conventional techniques known to those skilled in the art, or by using appropriate isotopically-labeled reagents in place of previously used non-labeled reagents. can be prepared by methods analogous to those described in the Examples as set forth below.

A compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, may contain one or more centers of asymmetry and thus, from the standpoint of absolute stereochemistry, as (R)- or (S)-, or in the case of amino acids ( Enantiomers, diastereomers and other stereoisomeric forms, which may be defined as D)- or (L)-, can be generated. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthetases or chiral reagents, or by conventional techniques. , for example using chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). includes the decomposition of Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When a compound is represented in its chiral form, it is understood that embodiments include, but are not limited to, the particular diastereomerically or enantiomerically enriched form. The chirality is not specified, but, if present, embodiments may include specific diastereomerically or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compound(s). As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

"Stereoisomers" refer to compounds that are made up of the same atoms held together by the same bonds, but have different three-dimensional structures that are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof, and includes “enantiomers”, which refer to two stereoisomers in which the molecules are non-superimposable mirror images of one another.

"Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the above compounds.

A “solvate” is formed by the interaction of a compound with a solvent. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

The term “prodrug” is defined in the pharmaceutical arts as a biologically inactive derivative of a drug that upon administration to the human body is converted according to some chemical or enzymatic pathway into a biologically active parent drug.

The term “combination antiretroviral therapy” (“cART”) refers to a combination or “cocktail” of antiretroviral drugs used to treat human viral infections, including HIV infection. As used herein, the terms “combination antiretroviral therapy” and “cART” encompass combinations and therapies often referred to as high activity antiretroviral therapy (HAART). HAART and cART combinations and therapies typically involve multiple, often two or more drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) , fusion inhibitors, CCR5 agonists and/or integrase inhibitors.

The terms “potential HIV reservoir”, “HIV potential reservoir”, “HIV reservoir”, “potential reservoir” and “potential HIV infection” refer to a condition in which resting CD4+ T lymphocytes or other cells are infected with HIV but are not actively producing HIV. refers to HIV infected cells that are currently inactive are referred to as “latent infected cells”. Antiretroviral therapy (ART) can reduce the level of HIV in the blood to undetectable levels, but potential reservoirs of HIV remain alive. When the latent infected cells are reactivated, the cells begin to produce HIV (HIV replication).

II. compound

The present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.

here,

R ¹ is —H, C _1-4 alkyl, or C _1-4 haloalkyl;

R ² is C _1-6 alkyl or C _1-6 haloalkyl;

R ³ _{is C 1-4} alkoxy optionally substituted with 1 R ^{X ;}

each R ^X is independently —OR ^Y , 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} or 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

R ^Y is C _1-4 alkyl, C _1-4 haloalkyl, or 5-10 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} ;

Q is N, CH, or CR ⁴ ;

or R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein

C _5-6 cycloalkyl and phenyl are each independently optionally substituted ^{with 1 to 3 R 5 ;}

each R ⁵ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with ^{1-3 R Z} , C _1-4 haloalkyl, C _1-4 alkoxy, —C (O)OH, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), - C(O)N(C _1-4 alkyl) ₂ , —N(H)C(O)C _1-4 alkyl, —S(O) ₂ C _1-4 alkyl, or optionally with ^{1-3 R Z} 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from substituted oxygen, nitrogen, and sulfur;

5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;}

each R ⁶ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with 1 phenyl optionally substituted with ^{1-3 R Z ;} C _1-4 haloalkyl, C _1-4 alkoxy, —S(O) ₂ C _1-4 alkyl; 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} or 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

5-6 membered heterocyclyl is optionally substituted with ^{1-3 R 7 ;}

R ⁷ is halogen, —OH, C _1-4 alkyl, C _1-4 alkoxy, or —C(O)R ⁸ ;

each R ⁸ _{is independently C 1-4} alkyl optionally substituted with —CN or —NH _{2 ;} C _1-4 haloalkyl; C _5-6 cycloalkyl, 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} or 5-10 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}

each R ^Z is independently —NH ₂ , C _1-4 alkyl, halogen, —CN, —OC _1-4 alkyl, C _1-4 haloalkyl, or —C(O)NH ₂ ;

이 아니다.with the proviso that formula I is

this is not

In certain embodiments of formula (I), Q is N, CH, or CR ⁴ . In certain embodiments of formula (I), Q is N. In certain embodiments of formula (I), Q is CH. In certain embodiments of formula (I), Q is CR ⁴ . In certain embodiments of formula (I), Q is CH or CR ⁴ .

In certain embodiments of formula (I), R ¹ is —H, C _1-4 alkyl, or C _1-4 haloalkyl. In certain embodiments of formula (I), R ¹ is —H or C _1-4 alkyl. In certain embodiments of formula (I), R ¹ is methyl. In certain embodiments of formula (I), R ¹ is ethyl. In certain embodiments of formula (I), R ¹ is propyl. In certain embodiments of formula (I), R ¹ is trifluoromethyl.

In certain embodiments of formula (I), R ² is C _1-6 alkyl or C _1-6 haloalkyl. In certain embodiments of formula (I), R ² is C _3-6 alkyl. In certain embodiments of formula (I), R ² is methyl. In certain embodiments of formula (I), R ² is ethyl. In certain embodiments of formula (I), R ² is propyl. In certain embodiments of formula (I), R ² is butyl. In certain embodiments of formula (I), R ² is pentyl. In certain embodiments of formula (I), R ² is hexyl.

In certain embodiments of formula (I), R ¹ is —H or C _1-4 alkyl; R ² is C _3-6 alkyl; Q is CR ⁴ ; R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein phenyl is optionally substituted with 1 to 3 halogen; 5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;} each R ⁶ is independently halogen, —OH, C _1-4 alkyl, or C _1-4 alkoxy; 5-6 membered heterocyclyl is optionally substituted with 1 to 3 -C(O)C _{1-4 alkyl.}

In certain embodiments of formula (I), R ¹ is —H or C _1-4 alkyl; R ² is C _3-6 alkyl; R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein phenyl is optionally substituted with 1 to 3 halogen; 5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;} each R ⁶ is independently halogen, —OH, C _1-4 alkyl, or C _1-4 alkoxy; 5-6 membered heterocyclyl is optionally substituted with 1 to 3 -C(O)R ^{8 , wherein each R 8} _{is independently C 1-4} alkyl optionally substituted with -CN or -NH ₂ , C _{1 -3} haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of formula (I), R ¹ is —H or C _1-4 alkyl; R ² is C _3-6 alkyl; R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein phenyl is optionally substituted with 1 to 3 halogen; 5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;} each R ⁶ is independently halogen, —OH, C _1-4 alkyl, or C _1-4 alkoxy; 5-6 membered heterocyclyl is optionally substituted with 1 to 3 -C(O)C _{1-4 alkyl.}

In certain embodiments of Formula (I), (II), or (III), R ³ _{is C 1-4} alkoxy optionally substituted with 1 to 3 R ^X , wherein R ^X is as defined herein. In certain embodiments of formula (I), (II), or (III), R ³ is an optionally substituted C _1-4 alkoxy, R 1 ^X, where R ^X is defined in this application. In certain embodiments of Formula (I), (II), or (III), R ³ _{is C 1-2} alkoxy optionally substituted with 1 to 3 R ^X , wherein R ^X is as defined herein.

In certain embodiments of Formula (I), (II), or (III), each R ^X is independently -OR ^Y , 1 to 3 selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1 to 3 R Z .} 5 to 6 membered heterocyclyl having 3 heteroatoms; phenyl optionally substituted with 1 to 3 R ^{Z ;} Or 1 to 3 to R ^Z optionally substituted by oxygen, nitrogen, and the aryl and 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from sulfur, and wherein R ^Y and R ^Z are defined in this Application. In certain embodiments of Formula (I), (II), or (III), each R ^X is independently OR ^Y , morpholino, phenyl, pyridinyl, pyrazolyl, or pyridazinyl, wherein each morpholino, phenyl, pyridinyl, pyrazolyl, and pyridazinyl are independently _{optionally substituted with —OCH 3} , C _1-3 alkyl, chloro, or fluoro; wherein R ^Y is —CH ₃ , —CH ₂ CF ₃ , or _{quinolinyl optionally substituted with —OCH 3} , C _1-3 alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), each R ^Y is independently C _1-4 alkyl, C _1-4 haloalkyl, or optionally substituted with 1 to 3 R ^{Z .} 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R ^Z is defined herein. In certain embodiments of Formula (I), (II), or (III), each R ^Y is independently —CH ₃ , —CH ₂ CF ₃ , or —OCH ₃ , C _1-3 alkyl, chloro, or quinolinyl optionally substituted with fluoro.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein C _5-6 cycloalkyl and phenyl are each independently optionally substituted ^{with 1 to 3 R 5 ;} ; 5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;} 5-6 membered heterocyclyl is optionally substituted with ^{1-3 R 7 ;} wherein R ⁵ , R ⁶ , and R ⁷ are defined in the present application.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ^{4 taken} _{together form C 5-6} cycloalkyl optionally substituted with 1-3 R ⁵ , wherein R ⁵ is as defined in this application. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a _{C 5-6 cycloalkyl.} In certain embodiments of Formula (I), (II), or (III), R ³ and R ^{4 taken} together form a 6 membered cycloalkyl.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R 7 .} Forms a 5-6 membered heterocyclyl having a, wherein R ⁷ is defined in the present application. In certain embodiments of Formula (I), (II), or (III), each R ⁷ is —C(O)R ⁸ , wherein R ⁸ _{is C 1} -C optionally substituted with —CN or —NH _{2 . 4} alkyl, C _1-3 haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl. In certain embodiments of Formula (I), (II), or (III), R ⁷ is —C(O)C _1-4 alkyl. In certain embodiments of Formula (I), (II), or (III), R ⁷ is —C(O)CH ₃ . In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form tetrahydropyridinyl optionally substituted with —C(O)R ^{8 , wherein R 8} is — _{C 1-4} alkyl optionally substituted with CN or —NH ₂ , C _1-3 haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a phenyl optionally substituted with 1 to 3 R ^{5 , wherein R 5} is defined herein have. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form phenyl. In certain embodiments of formula (I), (II), or (III), R ³ and R ⁴ _{together are C 1 -} optionally substituted with 1 to 3 chloro, fluoro, bromo, -CN, -OH pyrazolyl optionally substituted with ₂ alkyl, C _1-2 alkoxy, —C(O)C _1-2 alkyl, —C(O)OC _1-2 alkyl, or 1-3 C _{1-2 alkyl;} or phenyl optionally substituted with imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl.}

In certain embodiments of Formula (I), (II), or (III), each R ⁵ is independently halogen, —OH, —NH ₂ , —CN, C _1-4 alkyl, C _1-2 haloalkyl , C _1-4 alkoxy, -C(O)OH, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -C(O)NH ₂ , -C(O)NH (C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -N(H)C(O)C _1-4 alkyl, -S(O) ₂ C _1-4 alkyl . In certain embodiments of Formula (I), (II), or (III), each R ⁵ _{is independently C 1-2} alkyl, C optionally substituted with chloro, fluoro, bromo, —CN, —OH pyrazolyl optionally substituted with _1-2 alkoxy, -C(O)C _1-2 alkyl, -C(O)OC _1-2 alkyl, or 1-3 C _{1-2 alkyl;} or imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl.} In certain embodiments of Formula (I), (II), or (III), each R ⁵ is independently chloro, fluoro, bromo, —CN, —CH ₃ , —CF ₃ , —OCH ₃ , — C(O)CH ₃ , or —C(O)OCH ₃ . In certain embodiments of Formula (I), (II), or (III), each R ⁵ is independently chloro, fluoro, bromo, -CN, -CH ₃ , -OCH ₃ , -C(O) CH ₃ , or —C(O)OCH ₃ .

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R 6 .} Forms a 5-6 membered heteroaryl having a, wherein R ⁶ is defined in the present application. In certain embodiments of Formula (I), (II), or (III), each R ⁶ is independently halogen, —OH, C _1-4 alkyl, or C _1-4 alkoxy. In certain embodiments of Formula (I), (II), or (III), each R ⁶ is independently halogen, —OH, —CH ₃ , or —OCH ₃ . In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. do. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form pyrazinyl, pyridinyl or thienyl optionally substituted with 1 to 3 C _{1-2 alkyl} .

을 형성하고, 여기서 각각의 R⁵, R⁶, 또는 R⁷은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein each R ⁵ , R ⁶ , or R ⁷ is optionally present and as defined herein.

In certain embodiments, the compound of Formula (I) is a compound of Formula (II)

In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ^{4 taken} together form a 6 membered cycloalkyl. In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together represent tetrahydropyridinyl optionally substituted with 1 to 3 C(O)C _{1-2 alkyl.} to form In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together form phenyl optionally substituted with 1 to 3 fluoro. In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together form pyrazinyl, thienyl, or pyridinyl.

In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are C optionally substituted with 1 to 3 chloro, fluoro, bromo, -CN, -OH phenyl optionally substituted with _1-2 alkyl, C _1-2 alkoxy, -C(O)C _1-2 alkyl, or -C(O)OC _{1-2 alkyl.}

을 형성하고, 여기서 각각의 R⁵, R⁶, 또는 R⁷은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (II), R ³ and R ⁴ together are

wherein each R ⁵ , R ⁶ , or R ⁷ is optionally present and as defined herein.

In certain embodiments of compounds of Formula (I), the compound is a compound of Formula (III):

The groups R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^X , R ^Y , and R ^Z are as defined in formula (I) above, or as defined below, or any combination thereof. Thus, in certain embodiments of Formula (I), (II), or (III), R ³ _{is C 1-4} alkoxy optionally substituted with 1 to 3 R ^X , wherein R ^X is as defined herein have. Thus, in certain embodiments of Formula (I), (II), or (III), R ³ _{is C 1-4} alkoxy optionally substituted with one R ^X , wherein R ^X is as defined herein. In certain embodiments of Formula (I), (II), or (III), R ³ _{is C 1-2} alkoxy optionally substituted with 1 to 3 R ^X , wherein R ^X is as defined herein.

In certain embodiments of Formula (I), (II), or (III), each R ^X is independently -OR ^Y , 1 to 3 selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1 to 3 R Z .} 5 to 6 membered heterocyclyl having 3 heteroatoms; phenyl optionally substituted with 1 to 3 R ^{Z ;} Or 1 to 3 to R ^Z optionally substituted by oxygen, nitrogen, and the aryl and 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from sulfur, and wherein R ^Y and R ^Z are defined in this Application. In certain embodiments of Formula (I), (II), or (III), each R ^X is independently OR ^Y , morpholino, phenyl, pyridinyl, pyrazolyl, or pyridazinyl, wherein each morpholino, phenyl, pyridinyl, pyrazolyl, and pyridazinyl are independently _{optionally substituted with —OCH 3} , C _1-3 alkyl, chloro, or fluoro; wherein R ^Y is —CH ₃ , —CH ₂ CF ₃ , or _{quinolinyl optionally substituted with —OCH 3} , C _1-3 alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), each R ^Y is independently C _1-4 alkyl, C _1-4 haloalkyl, or optionally substituted with 1 to 3 R ^{Z .} 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R ^Z is defined herein. In certain embodiments of Formula (I), (II), or (III), each R ^Y is independently —CH ₃ , —CH ₂ CF ₃ , or —OCH ₃ , C _1-3 alkyl, chloro, or quinolinyl optionally substituted with fluoro.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein C _5-6 cycloalkyl and phenyl are each independently optionally substituted ^{with 1 to 3 R 5 ;} , 5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;} 5-6 membered heterocyclyl is optionally substituted with ^{1-3 R 7 ;} wherein R ⁵ , R ⁶ , and R ⁷ are defined in the present application.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ^{4 taken} _{together form C 5-6} cycloalkyl optionally substituted with 1-3 R ⁵ , wherein R ⁵ is as defined in this application. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a _{C 5-6 cycloalkyl.} In certain embodiments of formula (I), R ³ and R ^{4 taken} together form a 6 membered cycloalkyl.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R 7 .} Forms a 5-6 membered heterocyclyl having a, wherein R ⁷ is defined in the present application. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are 1 selected from oxygen, nitrogen, and sulfur optionally substituted with 1 to 3 —C(O)R ^{8 .} form a 5-6 membered heterocyclyl having to 3 heteroatoms, wherein R ⁸ _{is C 1-4} alkyl optionally substituted with -CN or -NH ₂ , C _1-3 haloalkyl, cyclopropyl, cyclobutyl , tetrahydropyranyl, thienyl optionally substituted with 1 to 3 C _{1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form tetrahydropyridinyl optionally substituted with —C(O)R ^{8 , wherein R 8} is — _{C 1-4} alkyl optionally substituted with CN or —NH ₂ , C _1-3 haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a phenyl optionally substituted with 1 to 3 R ^{5 , wherein R 5} is defined herein have. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form phenyl. In certain embodiments of formula (I), (II), or (III), R ³ and R ⁴ _{together are C 1 -} optionally substituted with 1 to 3 chloro, fluoro, bromo, -CN, -OH pyrazolyl optionally substituted with ₂ alkyl, C _1-2 alkoxy, —C(O)C _1-2 alkyl, —C(O)OC _1-2 alkyl, or 1-3 C _{1-2 alkyl;} or phenyl optionally substituted with imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl.}

In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together are 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R 6 .} form a 5 to 6 membered heteroaryl with R ⁶ as defined in the application. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form a 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. do. In certain embodiments of Formula (I), (II), or (III), R ³ and R ⁴ together form pyrazinyl, pyridinyl or thienyl optionally substituted with 1 to 3 C _{1-2 alkyl} .

을 형성하고, 여기서 각각의 R⁵, R⁶, 또는 R⁷은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein each R ⁵ , R ⁶ , or R ⁷ is optionally present and as defined herein.

을 형성하고, 여기서 R⁵는 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein R ⁵ is optionally present and as defined herein.

을 형성하고, 여기서 R⁷은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein R ⁷ is optionally present and as defined herein.

을 형성하고, 여기서 R⁷은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein R ⁷ is optionally present and as defined herein.

을 형성하고, 여기서 R⁶은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

, wherein R ⁶ is optionally present and as defined herein.

을 형성하고, 여기서 R⁵는 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

wherein R ⁵ is optionally present and as defined herein.

을 형성하고, 여기서 R⁶은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

, wherein R ⁶ is optionally present and as defined herein.

을 형성하고, 여기서 R⁶은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

, wherein R ⁶ is optionally present and as defined herein.

을 형성하고, 여기서 R⁶은 임의로 존재하고 본원에 정의된 바와 같다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

, wherein R ⁶ is optionally present and as defined herein.

을 형성한다.In certain embodiments of compounds of Formula (I), (II), or (III), R ³ and R ⁴ together are

to form

In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁵ is independently halogen, —OH, —NH ₂ , —CN, optionally substituted with ^{1-3 R Z .} C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -C(O)OH, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -C (O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -N(H)C(O)C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, or a 5- to 6-membered heteroaryl having one to three R ^Z as optionally 1 to 3 heteroatoms selected from the substituted oxygen, nitrogen, and sulfur, and wherein R ^Z is defined in this application. In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁵ _{is independently C 1-2} alkyl optionally substituted with chloro, fluoro, bromo, —CN, —OH. , C _1-2 alkoxy, -C(O)C _1-2 alkyl, -C(O)OC _1-2 alkyl, or pyrazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} or imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl.}

In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁶ is independently halogen, —OH, —NH ₂ , —CN, optionally substituted with ^{1-3 R Z .} _{C 1-4} alkyl optionally substituted with 1 phenyl; C _1-4 haloalkyl, C _1-4 alkoxy, —S(O) ₂ C _1-4 alkyl; 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} Or from 1 to 3 aryl of 5 to 6 membered heteroaryl having 1 to 3 hetero atoms selected from the optionally substituted with one oxygen, nitrogen, and sulfur, with R ^Z, wherein R ^Z is defined in the present application. In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁶ is independently C _1-2 alkyl.

In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁷ is independently halogen, —OH, C _1-4 alkyl, C _1-4 alkoxy, or —C(O). )R ⁸ , where R ⁸ is as defined in this application. In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁷ is independently —C(O)R ⁸ , wherein R ⁸ is optionally substituted with —CN or —NH _{2 .} C _1-4 alkyl; C _1-3 haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁸ _{is independently C 1-4} alkyl optionally substituted with —CN or —NH _{2 ;} C _1-4 haloalkyl; C _5-6 cycloalkyl, 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} Or from 1 to 3 aryl 5 to 10-membered heterocycle having 1 to 3 hetero atoms selected from the optionally substituted with one oxygen, nitrogen, and sulfur, with R ^Z, wherein R ^Z is defined in the present application. In certain embodiments of compounds of Formula (I), (II), or (III), each R ⁸ _{is independently C 1-4} alkyl, C _1-3 haloalkyl optionally substituted with —CN or —NH _{2 .} , cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of compounds of Formula (I), (II), or (III), each R ^Z is independently —NH ₂ , C _1-4 alkyl, halogen, —CN, —OC _1-4 alkyl, C _1-4 haloalkyl, or —C(O)NH ₂ .

, 또는 그의 제약상 허용되는 염으로부터 선택된다.In certain embodiments, the compound of formula (I) is

, or a pharmaceutically acceptable salt thereof.

, 또는 그의 제약상 허용되는 염으로부터 선택된다.In certain embodiments, the compound of formula (II) is

, or a pharmaceutically acceptable salt thereof.

, 또는 그의 제약상 허용되는 염으로부터 선택된다.In certain embodiments, the compound of formula (III) is

, or a pharmaceutically acceptable salt thereof.

As used herein, "a compound of formula (I)" includes a compound of formula (II) or (III).

III. composition

In certain embodiments, the present disclosure provides a compound of the present disclosure (eg, a compound of Formula (I), (II), or (III)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising

In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as set forth in more detail below.

Pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accordance with conventional practice. Tablets may contain excipients including glidants, fillers, binders, and the like. Aqueous compositions may be prepared in sterile form and may be generally isotonic when delivery other than oral administration is intended. All compositions optionally literature may contain excipients such as those set forth in [Rowe et al., Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009]. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. In certain embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form.

Compositions include those suitable for a variety of routes of administration, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Such methods include the step of bringing the active ingredient (eg, a compound of the disclosure or a pharmaceutical salt thereof) into association with one or more pharmaceutically acceptable excipients. Compositions can be prepared by bringing the active ingredient into uniform and intimate association with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21 ^st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Compositions described herein suitable for oral administration may be presented in discrete units (unit dosage form) including, but not limited to, capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

A pharmaceutical composition disclosed herein comprises one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions contain one or more excipients including sweetening, flavoring, coloring and preserving agents to provide palatable preparations. may contain. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract to provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with a wax.

The amount of active ingredient that may be combined with the inactive ingredient to prepare a dosage form may vary depending upon the intended subject being treated and the particular mode of administration. For example, in some embodiments, dosage forms for oral administration to humans may contain approximately 1-1000 mg of active substance formulated together with appropriate and convenient amounts of pharmaceutically acceptable excipients. In certain embodiments, pharmaceutically acceptable excipients vary from about 5 to about 95% (weight:weight) of the total composition.

In certain embodiments, a composition comprising a compound of the present disclosure (e.g., a compound of Formula (I), (II) or (III)) or a pharmaceutically acceptable salt thereof, in one variation, wherein the active ingredient is metabolized Contains no rate-affecting agents. Accordingly, a composition comprising a compound of the present disclosure may in one aspect affect the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure (e.g. For example, it is understood that it does not include agents that will slow down, interfere with or inhibit). In addition, any of the methods, kits, articles of manufacture, etc. detailed herein, in one aspect, affect the metabolism of a compound of the disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the disclosure. It is understood not to include agents that will affect (eg, slow down, interfere with or inhibit).

IV. Way

The present disclosure provides methods of treating a disease or condition that is responsive to modulation of a toll-like receptor (eg, TLR8 receptor). Without wishing to be bound by any one theory, it is believed that the compounds disclosed herein modulate the TLR8 receptor as an agonist. As will be appreciated by those of ordinary skill in the art, modulators of TLR8 may modulate other Toll-like receptors (eg, TLR7) to some extent. Thus, in certain embodiments, the compounds disclosed herein are also capable of modulating TLR7 to a measurable extent. In certain embodiments, compounds that modulate TLR8 to a greater extent than TLR7 are considered selective modulators of TLR8. Exemplary methods of measuring modulation of each of TLR7 and TLR8 of each compound are described in the Examples provided herein. In certain embodiments, the compounds disclosed herein are selective modulators of TLR8.

In certain embodiments, methods of modulating TLR8 are provided comprising administering to an individual (eg, a human) a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, methods of modulating TLR8 in vitro are provided.

In certain embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as a research tool, eg, for use in identifying modulators of TLR8.

In certain embodiments, the present disclosure provides for treatment or prevention of a disease or condition in an individual (eg, a human) in need thereof comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof. A method of treating or preventing a condition is provided. In certain embodiments, the method comprises administering one or more additional therapeutic agents. Treatment with a compound of the present disclosure typically results in stimulation of an immune response to the particular disease or condition being treated. Diseases or conditions contemplated by the present disclosure include those affected by modulation of toll-like receptors (eg, TLR8). In certain embodiments, a method of treating or preventing a disease or condition responsive to modulation of TLR8 is provided comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Exemplary diseases, disorders and conditions include, but are not limited to, autoimmune, inflammation, allergy, asthma, graft rejection, graft versus host disease (GvHD), infectious disease, cancer, and conditions involving immunodeficiency.

In certain embodiments, the infectious disease is hepatitis A, hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV), diseases such as severe acute respiratory syndrome (SARS), influenza, parainfluenza, cytomegalovirus, dengue, herpes simplex virus-1, herpes simplex virus-2, leishmania infection and respiratory syncytial virus. In certain embodiments, the infectious disease is hepatitis A, hepatitis B (HBV), hepatitis D (HDV), HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV), severe acute respiratory syndrome (SARS) , influenza, parainfluenza, cytomegalovirus, dengue, herpes simplex virus-1, herpes simplex virus-2, leishmania infection and respiratory syncytial virus.

In certain embodiments, there is provided a method of treating or preventing a viral infection comprising administering to an individual (eg, a human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one embodiment, the method can be used to elicit an immune response against multiple epitopes of a viral infection in a human. Induction of an immune response to a viral infection can be assessed using any technique known to one of ordinary skill in the art for determining whether an immune response has occurred. Methods of detecting an immune response suitable for the present disclosure include, inter alia, detecting a decrease in viral load or antigen in the serum of a subject, detection of IFN-gamma-secreting peptide specific T cells, and one or more liver enzymes, such as detection of elevated levels of alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, the detection of IFN-gamma-secreting peptide specific T cells is performed using an ELISPOT assay. Another embodiment comprises reducing the viral load associated with HBV infection, including a decrease as measured by PCR testing.

In certain embodiments, the present invention provides a method of enhancing the efficacy of a vaccine by co-administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (eg, a human) with the vaccine. . In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with a vaccine to boost an immune response by enabling production of higher amounts of antibody or allowing longer lasting protection. may be administered. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, may be used as a vaccine adjuvant to increase efficacy and response to immunization with a particular antigen. In certain embodiments, co-administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, with a vaccine may affect how antigens of the vaccine are presented to the immune system and may enhance the efficacy of the vaccine. .

In certain embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in medical therapy. In certain embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition responsive to modulation of TLR8. In certain embodiments, the disease or condition is a viral infection as set forth herein.

In certain embodiments, the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease or condition responsive to modulation of TLR8 is provided.

In certain embodiments, the present disclosure also provides for hepatitis B infection, comprising administering to an individual (eg, a human) infected with hepatitis B virus a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. A method of treating a viral infection is provided. While it is within the scope of the present disclosure to treat a person acutely infected with HBV, typically the subject suffers from a chronic hepatitis B infection.

The present disclosure also provides a method for treating hepatitis C virus infection comprising administering to an individual (eg, a human) infected with hepatitis C virus a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. provide a way While it is within the scope of the present disclosure to treat a person acutely infected with HCV, typically the subject suffers from chronic hepatitis C infection.

Treatment of HBV or HCV in accordance with the present disclosure typically results in stimulation of an immune response to HBV or HCV in an individual (eg, human) infected with HBV or HCV, respectively, and a viral load of HBV or HCV in the infected individual, respectively. causes a decrease. Examples of immune responses include production of antibodies (eg, IgG antibodies) and/or production of cytokines such as interferons that modulate the activity of the immune system. The immune system response may be a newly induced response, or it may be a boosting of an existing immune response. In particular, the immune system response may be seroconversion against one or more HBV or HCV antigens.

As described in more detail herein, a compound of the disclosure may be administered to an individual (eg, a human) infected with HBV or HCV in combination with one or more additional therapeutic agent(s). The additional therapeutic agent(s) may be administered to an infected individual (eg, a human) concurrently with a compound of the disclosure or before or after administration of a compound of the disclosure. For example, in certain embodiments, when used to treat or prevent HCV, the compounds of the present disclosure are interferon, ribavirin or analogs thereof, HCV NS3 protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 protease inhibitors , alpha-glucosidase 1 inhibitor, hepatoprotectant, nucleoside or nucleotide inhibitor of HCV NS5B polymerase, non-nucleoside inhibitor of HCV NS5B polymerase, HCV NS5A inhibitor, TLR7 agonist, cyclophilin inhibitor, HCV IRES and one or more additional therapeutic agent(s) selected from the group consisting of inhibitors, pharmacokinetic enhancers and other drugs for treating HCV, or mixtures thereof. Specific examples are described in more detail below.

Further, in certain embodiments, when used to treat or prevent HBV, the compounds of the present disclosure are HBV DNA polymerase inhibitors, Toll-like receptor 7 modulators, Toll-like receptor 8 modulators, Toll-like receptors. 7 and 8 modulators, toll-like receptor 3 modulators, interferon alpha ligands, HBsAg inhibitors, HbcAg targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV virus entry inhibitors, NTCP inhibitors, viral mRNA targeting antisense oligonucleotides, Short interfering RNA (siRNA), hepatitis B virus E antigen inhibitor, HBx inhibitor, cccDNA inhibitor, HBV antibody including HBV antibody targeting the surface antigen of hepatitis B virus, thymosin agonist, cytokine, nucleoprotein inhibitor (HBV core or capsid protein inhibitor), one or more additional therapeutic agent(s) selected from the group consisting of retinoic acid-inducible gene 1 stimulator, NOD2 stimulator, recombinant thymosin alpha-1 and hepatitis B virus replication inhibitor, and combinations thereof may be administered together with Specific examples are described in more detail below.

In certain embodiments, the present disclosure comprises administering to an individual (eg, a human) infected with hepatitis B virus or hepatitis C virus, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. , a method of ameliorating HBV infection or symptoms associated with HCV infection, wherein the therapeutically effective amount is sufficient to ameliorate HBV infection or symptoms associated with HCV infection. These symptoms include the presence of HBV virus particles (or HCV virus particles) in the blood, liver inflammation, jaundice, myalgia, weakness and fatigue.

In certain embodiments, the present disclosure comprises administering to an individual (eg, a human) infected with hepatitis B virus or hepatitis C virus, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. , a method of reducing the rate of progression of a hepatitis B virus infection or hepatitis C virus infection in a subject (eg, a human), wherein the therapeutically effective amount is the rate of progression of a hepatitis B virus infection or hepatitis C virus infection. is sufficient to reduce The rate of progression of infection can be tracked by measuring the amount of HBV virus particles or HCV virus particles in the blood.

In certain embodiments, the present disclosure provides an HBV infection or HCV infection comprising administering to an individual (eg, a human) infected with HBV or HCV a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Provided is a method of reducing the viral load associated with the disease, wherein the therapeutically effective amount is sufficient to reduce the HBV viral load or the HCV viral load in a subject.

In certain embodiments, the present disclosure provides for hepatitis B virus or hepatitis C in an individual comprising administering to the individual (eg, a human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. A method of inducing or boosting an immune response against a virus is provided, wherein a novel immune response to hepatitis B virus or hepatitis C virus is elicited in a subject, or has been previously directed against hepatitis B virus or hepatitis C virus. An existing immune response is boosted in the subject. Seroconversion to HBV or HCV can be induced in an individual. Examples of immune responses include the production of antibodies, such as IgG antibody molecules, and/or the production of cytokine molecules that modulate the activity of one or more components of the human immune system.

In certain embodiments, an immune response may be induced against one or more antigens of HBV or HCV. For example, the immune response is directed against HBV surface antigen (HBsAg), or against a small form of HBV surface antigen (small S antigen), or against an intermediate form of HBV surface antigen (intermediate S antigen), or a combination thereof. can be induced for As another example, an immune response can be induced against HBV surface antigen (HBsAg) and also against other HBV-derived antigens such as core polymerase or x-protein.

Induction of an immune response against HCV or HBV can be assessed using any technique known to one of ordinary skill in the art for determining whether an immune response has occurred. Methods of detecting an immune response suitable for the present disclosure include, inter alia, measuring the amount of HBV DNA or HCV DNA in the blood of a subject using, for example, a PCR assay and/or using a method such as an ELISA for anti- detecting a decrease in the viral load in the serum of an individual by measuring the amount of HBV antibody or anti-HCV antibody.

In certain embodiments, there is provided a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in treating or preventing an HBV infection. In certain embodiments, there is provided a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in treating or preventing an HCV infection. In certain embodiments, a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing HBV infection is provided. In certain embodiments, there is provided a compound of the present disclosure (eg, a compound of Formula I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing HCV infection.

In certain embodiments, the present disclosure also relates to a Retroviridae virus infection (eg, a Retroviridae ) in an individual comprising administering to the individual (eg, a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. For example, a method of treating HIV virus infection) is provided.

In certain embodiments, the present disclosure also includes administering to an individual (eg, a human) infected with the HIV virus, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprising administering to an HIV infection (e.g., For example, HIV-1 infection) is provided. In certain embodiments, the individual in need thereof is a human infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk of developing AIDS. In certain embodiments, the individual in need thereof is a human infected with HIV and who has developed AIDS.

In certain embodiments, there is provided a method of treating or preventing an HIV virus infection in an individual comprising administering to the individual (eg, a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, inhibiting replication of the HIV virus, treating AIDS, or AIDS in an individual comprising administering to the individual (eg, a human) a compound of the disclosure, or a pharmaceutically acceptable salt thereof A method of delaying the onset of

In certain embodiments, a method of preventing HIV infection in an individual is provided comprising administering to the individual (eg, a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of contracting the HIV virus, such as having one or more risk factors known to be associated with contracting the HIV virus.

In certain embodiments, a method of treating HIV infection in an individual is provided comprising administering to the individual (eg, a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to an individual (eg, a human) in need of treatment of an HIV infection, an HIV protease inhibitory compound, an HIV ratio of reverse transcriptase -nucleoside inhibitors, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and HIV A method of treating HIV infection in an individual is provided comprising administering in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of other drugs for treatment, and combinations thereof.

In certain embodiments, a compound of the invention is administered to a patient in which active HIV gene expression is inhibited by administration of antiretroviral therapy (including "combination antiretroviral therapy" or "cART").

In certain embodiments, a method of reducing potential HIV reservoirs in a human is provided comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of the present disclosure. In certain embodiments, the method further comprises administering one or more anti-HIV agents. In certain embodiments, the method further comprises administering an antiretroviral therapy (including a “combination antiretroviral therapy” or “cART”). In certain embodiments, active HIV gene expression in humans is inhibited by administration of antiretroviral therapy (including "combination antiretroviral therapy" or "cART").

In certain embodiments, medical therapy of HIV virus infection (eg, delaying replication of HIV-1 or HIV virus (eg, HIV-1) or onset of AIDS or AIDS in an individual (eg, human)) Provided is a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in

In certain embodiments, a compound of the present disclosure, or a pharmaceutical thereof, for use in the manufacture of a medicament for treating HIV virus infection or replication of HIV virus or AIDS or delaying the onset of AIDS in an individual (eg, a human) Phase acceptable salts are provided. One embodiment provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or curative treatment of HIV infection or AIDS, or for use in the therapeutic treatment or delaying onset of AIDS .

In certain embodiments, the use of a compound of the present disclosure (eg, a compound of Formula (I)) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for HIV virus infection in an individual (eg, a human) comprises: is provided In certain embodiments, there is provided a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV virus infection.

In certain embodiments, administration in the method of use is to an individual (eg, a human) in need of treatment. In certain embodiments, administration in the method of use is to an individual (eg, a human) at risk of developing AIDS.

Provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used in a method of treating HIV virus infection or replication of HIV virus or AIDS in an individual (eg, a human) or delaying the onset of AIDS. it is to do

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV in an individual in need thereof. to provide. In certain embodiments, the individual in need thereof is a human infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk of developing AIDS. In certain embodiments, the individual in need thereof is a human infected with HIV and who has developed AIDS.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of or delaying the onset of AIDS.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection.

In certain embodiments, the HIV infection is an HIV-1 infection.

Additionally, the compounds of the present disclosure are useful for the treatment of cancer or tumors (including dysplasia, such as uterine dysplasia). These include hematological malignancies, oral carcinomas (e.g., carcinoma of the lips, tongue, or pharynx), digestive organs (e.g., esophagus, stomach, small intestine, colon, large intestine or rectum), peritoneum, liver and biliary tract, pancreas, respiratory machinery, such as the larynx or lungs (small and non-small cells), bone, connective tissue, skin (eg, melanoma), breast, reproductive organs (fallopian tubes, uterus, cervix, testes, ovaries, or prostate), urinary tract ( bladder or kidney), brain and endocrine glands such as thyroid carcinoma. In summary, the compounds of the present disclosure are used to treat any neoplasm, including hematologic malignancies as well as all types of solid tumors. In certain embodiments, the compounds are useful for treating a cancer form selected from ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular cancer and colorectal cancer.

Hematological malignancies are broadly defined as proliferative disorders of blood cells and/or their progenitors, wherein these cells proliferate in an uncontrolled manner. Anatomically, hematological malignancies are divided into two primary groups: lymphoma - a malignant mass of lymphoid cells, primarily within, but not exclusively in, lymph nodes, and leukemia - typically derived from lymphoid or myeloid cells and , neoplasms affecting mainly the bone marrow and peripheral blood. Lymphomas can be subdivided into Hodgkin's disease and non-Hodgkin's lymphoma (NHL). The latter group is clinically (eg, aggressive lymphoma, indolent lymphoma), histologically (eg, follicular lymphoma, mantle cell lymphoma) or of malignant cell origin (eg, B lymphocytes, T It contains several distinct entities that can be distinguished on the basis of lymphocytes). Leukemias and related malignancies include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Other hematological malignancies include plasma cell dysentery, including multiple myeloma, and myelodysplastic syndrome.

In certain embodiments, the compounds of the present disclosure are useful for the treatment of B-cell lymphoma, lymphoplasmacytic lymphoma, fallopian tube cancer, head and neck cancer, ovarian cancer, and peritoneal cancer.

In certain embodiments, the compounds of the present disclosure are useful for the treatment of hepatocellular carcinoma, gastric cancer, and/or colorectal cancer. In certain embodiments, the compounds of the present disclosure are useful for the treatment of prostate cancer, breast cancer and/or ovarian cancer. In certain embodiments, the compounds of the present disclosure are useful for the treatment of relapsed or metastatic squamous cell carcinoma.

In certain embodiments, treating a hyperproliferative disease comprising administering to an individual (eg, a human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. method is provided. In certain embodiments, the hyperproliferative disease is cancer. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is selected from ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular cancer and colorectal cancer. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is Hodgkin's lymphoma. In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certain embodiments, the cancer is B-cell lymphoma. In certain embodiments, the cancer is B-cell lymphoma; fallopian tube cancer, head and neck cancer, ovarian cancer and peritoneal cancer. In certain embodiments, the method further comprises administering one or more additional therapeutic agents as described in more detail herein.

In certain embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer and/or recurrent or metastatic squamous cell carcinoma. In certain embodiments, the cancer is prostate cancer, breast cancer and/or ovarian cancer. In certain embodiments, the cancer is hepatocellular carcinoma, gastric cancer, and/or colorectal cancer. In certain embodiments, the cancer is relapsed or metastatic squamous cell carcinoma.

In some embodiments, administration in the method of use is to an individual (eg, a human) in need of treatment.

Further examples of diseases, disorders or conditions include psoriasis, systemic lupus erythematosus, and allergic rhinitis.

In one embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is for use in a method of treating a hyperproliferative disease (eg, cancer) in an individual (eg, a human).

Also provided herein is the use of a compound of the present disclosure (eg, a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a hyperproliferative disease (eg, cancer) do.

V. Administration

One or more of the compounds of the present disclosure (also referred to herein as active ingredients) may be administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

A compound of the present disclosure, such as a compound of formula (I), can be administered for a desired period of time or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, depending on an effective dosing regimen for the individual. or for at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the subject's life.

The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment based on the judgment of the administering physician.

The compound can be administered to a subject (eg, a human) in an effective amount. In certain embodiments, the compound is administered once daily.

In certain embodiments, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human in a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 A method of treating or preventing a disease or condition in a human is provided comprising administering in combination with 3 to 3, or 1 to 4) additional therapeutic agents. Because modulators of TLR8 can be used to treat a variety of diseases or conditions, the specific identity of the additional therapeutic agent will depend on the particular disease or condition being treated.

A compound of Formula (I), (II), or (III) may be administered by any useful route and means, such as oral or parenteral (eg, intravenous) administration. A therapeutically effective amount of a compound of Formula (I), (II), or (III) is from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 0.0001 mg/kg body weight per day. about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg per day /kg body weight, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 μg to about 30 mg per day, or such as from about 30 μg to about 300 per day is μg.

A compound of the present disclosure may be combined with one or more additional therapeutic agents at any dosage of a compound of the present disclosure (eg, 1 mg to 1000 mg of compound). A therapeutically effective amount of a compound of formula (I), (II), or (III) is from about 0.01 mg per dose to about 1000 mg per dose, such as from about 0.01 mg per dose to about 100 mg per dose, or such as about 0.1 per dose. mg to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose. Another therapeutically effective amount of a compound of formula (I), (II), or (III) is about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg. Another therapeutically effective amount of a compound of formula (I), (II), or (III) is about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours or once every 24 hours. A single dose may also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose may also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once weekly. A single dose may also be administered once a month.

The frequency of administration of the compound of formula (I), (II), or (III) will be determined by the needs of the individual patient and may be, for example, once a day or twice a day or more. Administration of the compound is continued for as long as necessary to treat the HBV or HCV infection. For example, Compound I may be administered to a human infected with HBV or HCV for a period of 20 days to 180 days, or for example for a period of 20 days to 90 days, or for example for a period of 30 days to 60 days. can

Administration is intermittent, wherein the patient receives a daily dose of a compound of formula (I), (II), or (III) for a period of at least several days, and then the patient does not receive a daily dose of the compound for a period of at least several days. can For example, a patient may be given a dose of the compound every other day or three times a week. As another example, the patient receives a dose of the compound daily for a period of 1 to 14 days, then the patient does not receive a dose of the compound for a period of 7 to 21 days, followed by a subsequent period (eg, 1 to 14). day), the patient may again receive a daily dose of the compound. Alternating periods of administration of the compound followed by non-administration of the compound may be repeated as clinically required to treat the patient.

In one embodiment, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents and a pharmaceutically acceptable excipient. There is provided a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of the present disclosure in combination with one or more (eg, 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents. or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 1, 2, 3, 4 or more additional therapeutic agents. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The 1, 2, 3, 4 or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or may be selected from different classes of therapeutic agents.

In certain embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as simultaneous or sequential therapy. When administered sequentially, the combination may be administered in two or more administrations.

In certain embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, a solid dosage form for oral administration.

In certain embodiments, a compound of the present disclosure is administered in combination with one or more additional therapeutic agents. Co-administration of a compound of the present disclosure and one or more additional therapeutic agents generally results in a therapeutically effective amount of a compound disclosed herein and one or more additional therapeutic agents, both present in the body of the patient and a compound of the present disclosure and Simultaneous or sequential administration of one or more additional therapeutic agents.

Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, eg, herein within seconds, minutes, or hours of administration of the one or more additional therapeutic agents. administration of the disclosed compounds. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents after a period of hours (eg, 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a period of hours (eg, 1-12 hours) after a unit dose of a compound of the present disclosure is administered.

VI. Combination therapy for HBV

In certain embodiments, a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to a human suffering from or at risk of HBV infection in a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4). , 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In one embodiment, a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to a human suffering from or at risk of HBV infection in a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4). , 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

In certain embodiments, the present disclosure provides to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount of one or more suitable for treating an HBV infection (e.g., for example 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 1, 2, 3, 4 or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The 1, 2, 3, 4 or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

Administration of HBV combination therapy

In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as simultaneous or sequential therapy. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more therapeutic agents such that a therapeutically effective amount of each agent is present in the body of a patient. .

Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. The compounds disclosed herein may be administered within seconds, minutes, or hours of administration of the one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, followed by a period of several hours (eg, 1-12 hours), followed by a unit dose of one or more additional therapeutic agents is administered. In other embodiments, a unit dose of one or more additional therapeutic agents is first administered, followed by a period of hours (eg, 1-12 hours), followed by a unit dose of a compound disclosed herein is administered.

In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

In certain embodiments, the compound of formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV.

In certain embodiments, such tablets are suitable for once daily administration.

HBV combination therapy

In this embodiment, the additional therapeutic agent may be an anti-HBV agent. For example, additional therapeutic agents include HBV combination drugs, other drugs to treat HBV, 3-dioxygenase (IDO) inhibitors, viral mRNA targeting antisense oligonucleotides, apolipoprotein A1 modulators, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, HBcAg targeting compounds, hepatitis B core antigen (HBcAg) targeting Compounds, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytokines, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesoids X receptor agonist, gene modifier or editor, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBV antibody, HBV DNA polymerase inhibitor, HBV replication inhibitor, HBV RNAse inhibitor, HBV vaccine, HBV virus entry inhibitor, HBx inhibitor, B hepatitis large envelope protein modulator, hepatitis B large envelope protein stimulator, hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitor, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitor, hepatitis B virus E Antigen inhibitor, hepatitis B virus replication inhibitor, hepatitis virus structural protein inhibitor, HIV-1 reverse transcriptase inhibitor, hyaluronidase inhibitor, IAP inhibitor, IL-2 agonist, IL-7 agonist, immunoglobulin efficacy agent, immunoglobulin G modulator, immunomodulator, indoleamine-2, inhibitor of ribonucleotide reductase, interferon agonist, interferon alpha 1 ligand, interferon alpha 2 ligand, interferon alpha 5 ligand modulator, interferon alpha ligand, interferon alpha ligand modulator, interferon alpha receptor ligand, interferon beta ligand, interferon ligand, interferon receptor modulator, interleukin -2 ligand, ipi4 inhibitor, lysine demethylase inhibitor, histone demethylase inhibitor, KDM5 inhibitor, KDM1 inhibitor, killer cell lectin-like receptor subfamily G member 1 inhibitor, lymphocyte-activating gene 3 inhibitor, lymphotoxin beta receptor activation agent, microRNA (miRNA) gene therapy agent, modulator of Axl, modulator of B7-H3, modulator of B7-H4, modulator of CD160, modulator of CD161, modulator of CD27, modulator of CD47, modulator of CD70, modulator of GITR , modulator of HEVEM, modulator of ICOS, modulator of Mer, modulator of NKG2A, modulator of NKG2D, modulator of OX40, modulator of SIRPalpha, modulator of TIGIT, modulator of Tim-4, modulator of Tyro, Na+-taurocholate co transport polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, peptidylprolyl isomerase inhibitors, phosphatidyl Inositol-3 kinase (PI3K) inhibitor, recombinant scavenger receptor A (SRA) protein, recombinant thymosin alpha-1, retinoic acid-inducible gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitor, RNA DNA Polymerase inhibitor, short interfering RNA (siRNA), short synthetic hairpin RNA (sshRNA), SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinase inhibitor, stimulator of interferon gene agonist (STING), stimulator of NOD1, T cell surface sugar protein CD28 inhibitor, T-cell surface glycoprotein CD8 modulator, thymosin agonist, thymosin alpha 1 ligand, Tim-3 inhibitor, TLR3 agonist, TLR7 agonist, TLR9 agonist, TLR9 gene stimulator, toll-like receptor ( TLR) modulators, viral ribonucleotide reductase inhibitors, zinc finger nucleases or synthetic nucleases (TALENs), and combinations thereof It can be selected from the group of Jin.

In certain embodiments, the compound of formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablet comprises another active ingredient for treating HBV, such as a 3-dioxygenase (IDO) inhibitor, an apolipoprotein A1 modulator, an arginase inhibitor, a B- and T-lymphocyte attenuator inhibitor, Bruton. Tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, HBcAg targeting compounds, hepatitis B core antigen (HBcAg) targeting compounds, core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesoid X receptor agonists , HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B hepatitis structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitor, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitor, hepatitis B virus E antigen inhibitor, hepatitis B virus replication inhibitor, hepatitis virus structural protein inhibitor, HIV -1 reverse transcriptase inhibitor, hyaluronidase inhibitor, IAP inhibitor, IL-2 agonist, IL-7 agonist, immunomodulatory agent, indoleamine-2 inhibitor, inhibitor of ribonucleotide reductase, interleukin-2 ligand, ipi4 inhibitor, lysine demethylase inhibitor, histone demethylase inhibitor, KDM1 inhibitor, KDM5 inhibitor, killer cell lectin-like receptor subfamily G member 1 inhibitor, lymphocyte-activating gene 3 inhibitor, lymphotoxin beta receptor activator, of Axl modulator, modulator of B7-H3, modulator of B7-H4, modulator of CD160, modulator of CD161, modulator of CD27, modulator of CD47, C D70 modulator, GITR modulator, HEVEM modulator, ICOS modulator, Mer modulator, NKG2A modulator, NKG2D modulator, OX40 modulator, SIRPalpha modulator, TIGIT modulator, Tim-4 modulator, Tyro modulator , Na+-taurocholate cotransport polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, peptidylprolyl isomerase inhibitors , phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors , stimulator of interferon gene agonist (STING), stimulator of NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surface glycoprotein CD8 modulator, thymosin agonist, thymosin alpha 1 ligand, Tim-3 inhibitor, TLR3 agonist agents, TLR7 agonists, TLR9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is an HBV combination drug, HBV vaccine, HBV DNA polymerase inhibitor, immunomodulator Toll-like receptor (TLR) modulator, interferon alpha receptor ligand, hyaluronida. agent inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV virus entry inhibitors, viral mRNA targeting antisense oligonucleotides, short interfering RNA (siRNA) and ddRNAi endonuclease modulator, ribonucleotide reductase inhibitor, HBV E antigen inhibitor, covalent closed circular DNA (cccDNA) inhibitor, farnesoid X receptor agonist, HBV antibody, CCR2 chemokine antagonist, thymosin agonist, cytokine, nuclear protein modulator, retinoic acid-inducible gene 1 stimulator, NOD2 stimulator, phosphatidylinositol 3-kinase (PI3K) inhibitor, indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, PD-1 inhibitor, PD-L1 inhibitor , recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitor, KDM inhibitor, HBV replication inhibitor, arginase inhibitor, and 1, 2, 3, 4 or more additional therapeutic agents selected from other HBV drugs is combined with

HBV combination drugs

Examples of combination drugs for the treatment of HBV include TRUVADA ^® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800 (INO-9112 and RG7944).

other HBV drugs

Examples of other drugs for the treatment of HBV include alpha-hydroxytropolone, amdoxorine, beta-hydroxycytosine nucleoside, CCC-0975, elbucitabine, ezetimibe, cyclosporin A, gentiopicrin ( Genthiopicroside), JNJ-56136379, nitazoxanide, birinapant, NOV-205 (molic acid, BAM-205), oligotide, mibotylate, peron, GST-HG-131, levamisole, car Shuning, Alloperon, WS-007, Y-101 (Tifentai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, Oleanolic acid, HepB-nRNA, cTP-5 (rTP-5) ), HSK-II-2, HEISCO-106-1, HEISCO-106, Hefvarna, IBPB-006IA, Hepuinpen, Dascloster 0014-01, ISA-204, Jiangantai (Ganxikan), MIV- 210, OB-AI-004, PF-06, Picroside, Darth Closter-0039, Hepulantai, IMB-2613, TCM-800B, Reduced Clutathione, RO-6864018, RG-7834, UB-551 , and ZH-2N, and US20150210682 (Roche), US 2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche) ), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche).

HBV vaccine

HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexasim, Heplixab, Mosquirix, DTwP-HBV Vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV Vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhey, Hepatitis B Prevention Vaccine (Adbox Super D), Hepatrol-07 , GSK-223192A, ENGERIX B ^® , Recombinant Hepatitis B Vaccine (Intramuscular, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Hansenula Polymorpha Yeast, Muscle) Nae, Hualan Biological Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Vimugen, Euforavac, Eutravac, Anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix- DTaP-IPV-Hep B-Hib, PentaBio vaccine DTP-HB-Hib, Combak 4, Twinrix, Uvax-B, Tritanlix HB, Infanrix Hep B, Combax, DTP-Hib-HBV vaccine, DTP -HBV Vaccine, Lee Tai, Heberbiovac HB, Trivac HB, Gervax, DTwP-Hep B-Hib Vaccine, Bilib, Hepabox-Gene, Superbox, Combak 5, Shanbak-B, Hebsulin, Recombi Box HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAg vaccine, and DTaP-rHB-Hib vaccine.

Examples of vaccines for treating HBV include HBsAg-HBIG complex, ARB-1598, Bio-Hep-B, Nasbac, abi-HB (intravenous), ABX-203, Tetrabuhey, GX-110E, GS-4774, peptide vaccine (Epsilon PA-44), Hepatrol-07, Nasvac (Nasterab), IMP-321, Vevac, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB , VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, mega-CD40L-adjuvant vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP -based therapeutic vaccines (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, Cronvac-B, TG-1050, and Lm HBV.

HBV DNA polymerase inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA ^® ), emtricitabine (EMTRIVA ^® ), tenofovir ^{disoproxil fumarate (VIREAD ®} ), te nofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir ^{, entecavir (BARACLUDE ®} ), entecavir maleate, telbivudine (TYZEKA ^® ), pradefovir, Clevudine, Ribavirin, Lamivudine (Epivir-HBV(EPIVIR-HBV) ^® ), Phosphazide, Famciclovir, Fusoline, Metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

immunomodulators

Examples of immunomodulators include lintatolimod, imidol hydrochloride, ingaron, dermavir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivatives mycophenol late mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), gepon, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, and IR-103.

Toll-like receptor (TLR) modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulating agent comprises rinta Tolly mode, poly -ICLC, Reebok hand (RIBOXXON) ^®, O poksim, Reebok core ^{(RIBOXXIM) ®, IPH-33} , MCT-465, MCT-475 and ND-1.1.

Examples of TLR7 modulators are GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M -052, Rimtop, TMX-30X, TMX-202, RG-7863, RG-7795, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences) compounds disclosed in

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and US20140045849 (Janssen), US20140073642 (Janssen) , WO2014/056953 (Jansen), WO2014/076221 (Jansen), WO2014/128189 (Jansen), US20140350031 (Jansen), WO2014/023813 (Jansen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma) ), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (VentiRX Pharma), US2012082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Vential X Pharma), US20140088085 (VentiRX Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics).

Examples of TLR9 modulators are BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, Agatolimod, DIMS-9054, DV -1079, DV-1179, AZD-1419, leptolimod (MGN-1703), ritenimod, and CYT-003-QbG10.

Interferon Alpha Receptor Ligand

Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A ^® ), pegylated interferon alpha-2a (PEGASYS ^® ), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN ) ^® ), Veldona, Infradur, Loferon-A, YPEG-Interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Infradur (Interferon Gamma), rSIFN-co (recombinant super compound interferon), Y-peginterferon alfa-2b (YPEG-rhIFN alpha-2b), MOR-22, pegginterferon alfa-2b (PEG-INTRON ^® ), bioferon, novaferon, inmu TAG (Inferon) ^{, MULTIFERON ®} , interferon alpha-n1 (HUMOFERON ^® ), interferon beta-1a (AVONEX ^® ), chaperone, interferon alpha-2b (Axxo), alpha Peron, Interferon alpha-2b (BioGeneric Pharma), Interferon-alpha 2 (CJ), Laperonum, Vipeg, Blauferon-A, Blauferon-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, Interferon alpha-2b (IFN, Laboratorios Bioprofarma), Alpha Interferona 2b, Calperon, Pegnano, Peronsure, Peggyhep, Interferon alfa 2b (Zydus-Cadilla), Interferon alfa 2a, Optipeg A, Realpa 2B, Reliperon, Interferon alfa-2b (Amega), Interferon alfa-2b (Virchow), ropeginterferon alpha-2b, rHSA-IFN alpha-2a (recombinant human serum albumin interferon alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha-(1b, 2a, 2b) ), peginterferon alfa-2b (Amega), peginterferon alfa-2a, reaferon-EC, proquiferon, uniferon, uripron, interferon alfa-2 b (Changchun Institute of Biological Products), Anterferon, Shanferon, Rayferon, Shang Seng Lei Tai, Intefen, Sinogen, Fukangtai, Pegstat, rHSA-IFN Alpha- 2b and Interrapa (Interpa).

hyaluronidase inhibitors

Examples of hyaluronidase inhibitors include astorimers.

Hepatitis B surface antigen (HBsAg) inhibitor

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165 , REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, and REP-9AC'.

Examples of inhibitors of HBsAg secretion include BM601.

Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, belatacept, PSI-001, PRS-010, probody mAb, tremelimumab, and JHL Includes -1155.

Cyclophylline inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and US8513184 (Gilliad Sciences), US20140030221 (Gilliad Sciences), US20130344030 (Gilliad Sciences), and US20130344029 (Gilliad Sciences).

HBV virus entry inhibitor

Examples of inhibitors of HBV virus entry include Myrcludex B.

Antisense oligonucleotides targeting viral mRNA

Examples of viral mRNA targeting antisense oligonucleotides include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404.

short interfering RNA (siRNA) and ddRNAi.

Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease modulators

Examples of endonuclease modulators include PGN-514.

Ribonucleotide reductase inhibitors

Examples of inhibitors of ribonucleotide reductase include trimidox.

HBV E antigen inhibitor

Examples of HBV E antigen inhibitors include ugonin.

covalent closed circular DNA (cccDNA) inhibitors

Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

Farnesoid X receptor agonists

Examples of farnesoid x receptor agonists such as EYP-001.

HBV antibody

Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV hepabulin SN, and fully human monoclonal antibody therapy (hepatitis B virus infection). , Humaps Biomed).

Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include Jutectra, Shang Saint Gandhi, Uman Vik (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, Hepagam. B, Igantib, niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products) and Poveta (BT-088).

fully human monoclonal antibody such as HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

thymosin agonist

Examples of thymosin agonists include thymalfasin, recombinant thymosin alpha 1 (GenScience).

cytokine

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (sengen neptunus), IL-15, IL-21, IL-24, and selmo. including leukin.

nucleoprotein modulators

The nucleoprotein modulator may be an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, morphothiadin mesylate, JNJ-379, and DVR-23. capsid assembly inhibitors such as AB-423.

Examples of capsid inhibitors include US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 ( Janssen), WO2014033167 (Jansen), WO2015/059212 (Jansen), WO2015118057 (Jansen), WO2015011281 (Jansen), WO2014184365 (Jansen), WO2014184350 (Jansen), WO2014161888 (Jansen), WO2013096744 (Novira), US20150225355 (Novira) ), US20140178337 (Novira), US20150315159 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Nobira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche).

Retinoic acid-inducible gene 1 stimulator

Examples of stimulators of retinoic acid-inducible gene 1 include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170, RGT- includes 100.

NOD2 stimulant

Examples of stimulants of NOD2 include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelarisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigocertib, rigocertib sodium, EN-3342, TGR-1202, Alfelicip, Dubelisip, IPI-549, UCB-5857, Tasselisip, XL-765, Gedatolisip, ME-401, VS-5584, Copanliship, CAI Oh Rotate, Perifosine, RG-7666, GSK-2636771, DS-7423, Panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, Pilaralisib, BAY-1082439, Puquitinib Mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, Sonolisip, LY-3023414, SAR-260301, TAK-117, HMPL-689 , tenalisib, voxtalisi, and CLR-1401.

Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indoxymod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218 and US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences Inc.), and WO2015188085 (Flexus Biosciences, Inc.). ).

PD-1 inhibitors

Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110 and mDX-400. include

PD-L1 inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

Recombinant thymosin alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylated thymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059 , BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, Sfebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP -7536, M-2951, TAK-020, AC-0025, and US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical).

KDM inhibitors

Examples of KDM5 inhibitors are WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel) disclosed compounds.

Examples of KDM1 inhibitors include the compounds disclosed in US9186337B2 (Orizon Genomics), and GSK-2879552, RG-6016, ORY-2001.

HBV replication inhibitors

Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and cinganthi.

Arginase inhibitors

Examples of arginase inhibitors include CB-1158, C-201, and resminostat.

HBV combination therapy

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is adefovir (Hepcera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (Baraclud®), telbivudine (Taizeca®) or lamivudine (Efivir-HBV) ®) with 1, 2, 3 or 4 additional therapeutic agents selected from the group consisting of In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is adefovir (Hepcera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (Baraclud®), telbivudine (Taizeca®) or lamivudine (Efivir-HBV) ®) in combination with a first additional therapeutic agent selected from the group consisting of In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) ), and a pharmaceutical composition comprising in combination with a pharmaceutically acceptable carrier, diluent or excipient.

HBV DNA polymerase inhibitor combination therapy

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, and at least one additional therapeutic agent selected from the group consisting of: an immunomodulatory agent, a TLR modulator, Interferon alpha receptor ligand, hyaluronidase inhibitor, recombinant IL-7, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBcAg targeting compound, cyclophilin inhibitor, HBV vaccine, HBV viral entry inhibitor, NTCP inhibitor, viral mRNA targeting antisense oligonucleotide , siRNA, miRNA gene therapy agent, endonuclease modulator, ribonucleotide reductase inhibitor, hepatitis B virus E antigen inhibitor, recombinant SRA protein, src kinase inhibitor, HBx inhibitor, cccDNA inhibitor, sshRNA, of hepatitis B virus HBV antibodies, including HBV antibodies and bispecific antibodies targeting the surface antigen and the "antibody-like" therapeutic protein (e.g. DART ^®, Duo ^® body, byte ^®, XmAb ^{®, ®} TANDBERG Ab, Fab derivative, or similar TCR- antibody), CCR2 chemokine antagonist, thymosin agonist, cytokine, nucleoprotein modulator (HBV core or capsid protein modulator), retinoic acid-inducible gene 1 stimulator, RIG-I-like receptor stimulator, NOD2 stimulator, NOD1 modulator Stimulant, arginase inhibitor, STING agonist, PI3K inhibitor, lymphotoxin beta receptor activator, natural killer cell receptor 2B4 inhibitor, lymphocyte-activating gene 3 inhibitor, CD160 inhibitor, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda , recombinant thymosin alpha-1, BTK inhibitor, TIGIT modulator, CD47 modulator, SIRPal Modulator of leeks, modulator of ICOS, modulator of CD27, modulator of CD70, modulator of OX40, epigenetic modifier, modulator of NKG2D, modulator of Tim-4, modulator of B7-H4, modulator of B7-H3, modulator of NKG2A , modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, genetic modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic Nucleases (TALENs), IAP inhibitors, SMAC mimetics, KDM5 inhibitors, IDO inhibitors, and hepatitis B virus replication inhibitors.

In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of: an immunomodulatory agent, a TLR modulator, a HBsAg inhibitor, HBV antibodies and "antibody-like" therapeutic proteins, including HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies and bispecific antibodies targeting the surface antigen of the hepatitis B virus, such as DART ^® , Duobody ^® , Bite ^® , XmAb ^{®, ®} TANDBERG Ab, Fab derivatives, TCR- or similar antibody), a cycloalkyl pilrin inhibitor, a retinoic acid-inducible gene 1 of the stimulant, a stimulant of RIG-I-like receptor, PD-1 inhibitors, PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO inhibitor, and a NOD2 stimulator, and one or two additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, B HBV antibody, siRNA, miRNA gene therapy agent, sshRNA, KDM5 inhibitor, and nucleoprotein modulator (HBV core or capsid protein modulator) targeting the surface antigen of hepatitis virus.

In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: an HBV viral entry inhibitor, an NTCP inhibitor, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

HBV drug combination therapy

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} ( ^{Taizeca ®} ) or lamivudine (Epivir-HBV ^® ), and at least a second additional therapeutic agent selected from the group consisting of: an immunomodulatory agent, a TLR modulator, an interferon alpha receptor ligand, a hyaluronidase inhibitor , recombinant IL-7, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBcAg targeting compound, cyclophilin inhibitor, HBV vaccine, HBV virus entry inhibitor, NTCP inhibitor, viral mRNA targeting antisense oligonucleotide, siRNA, miRNA gene therapy agent, endonuclease Clase modulator, inhibitor of ribonucleotide reductase, hepatitis B virus E antigen inhibitor, recombinant SRA protein, src kinase inhibitor, HBx inhibitor, cccDNA inhibitor, sshRNA, HBV antibody and bispecific targeting the surface antigen of hepatitis B virus HBV antibodies, including antibody and "antibody-like" therapeutic protein (e.g. DART ^®, Duo ^® body, byte ^®, XmAb ^{®, ®} TANDBERG Ab, Fab derivatives, and similar antibodies TCR-), CCR2 chemokine antagonists, thymosin efficacy Agents, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), retinoic acid-inducible gene 1 stimulator, RIG-I-like receptor stimulator, NOD2 stimulator, NOD1 stimulator, IDO inhibitor, recombinant thymosin alpha- 1, arginase inhibitor, STING agonist, PI3K inhibitor, lymphotoxin beta receptor activator, natural killer cell receptor 2B4 inhibitor, lymphocyte-activating gene 3 inhibitor, CD160 inhibitor, ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitor, PEG-interferon lambda, BTK inhibitor, TIGIT modulator, CD47 modulator, SIRPalpha modulator, ICOS modulator, CD27 modulator, CD70 modulator, OX40 modulator, NKG2D modulator, Tim-4 modulator, B7 -H4 modulator, B7-H3 modulator, NKG2A modulator, GITR modulator, CD160 modulator, HEVEM modulator, CD161 modulator, Axl modulator, Mer modulator, Tyro modulator, genetic modifier or editor such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), IAP inhibitors, SMAC mimetics, KDM5 inhibitors, and hepatitis B virus replication inhibitors.

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} ( ^{Taizeca ®} ) or lamivudine (Epivir-HBV ^® ), and at least a second additional therapeutic agent selected from the group consisting of: peginterferon alfa-2b (PEG-intron ^® ), multiferon ^® , interferon alfa-1b (half-gen ^®), interferon alfa -2b (intron A ^®), PEG Chemistry interferon alpha -2a (Pegasys ^®), interferon alpha -n1 (hyumo Peron ^®), ribavirin, interferon beta -1a (AVONEX ^® ), Bioferon, Ingaron, Inmutag (Inferon), Algheron, Loferon-A, Oligotide, Zutectra, Chaperon, Interferon alpha-2b (AXXO), Alphaperon, Interferon alpha-2b (Biogeneric Pharma) ), Peron, Interferon-alpha 2 (CJ), Vevac, Laperonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon- B, interferon alfa-2b (IFN, laboratory biopropharma), alfa interferona 2b, calperon, pegnano, peronsure, peggyhep, interferon alfa 2b (Zydus-cadilla), optipeg A, Realpa 2B, reliperon, interferon alpha-2b (Amega), interferon alpha-2b (virhyo), peginterferon alpha-2b (Amega), reaferon-EC, proquiferon, uniferon, uripron, Interferon alpha-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, Interleukin-2 (IL-2, Immunex), Recombinant Human Interleukin-2 (Shenzhen Neptunus), Rayferon , Ka Shuning, Shang Seng Lei Tai, Intefen, Sinogen, Fu Kang Tai, Alloperon, and Celmorukin.

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} ( ^{Taizeca ®} ), or lamivudine (Efivir-HBV ^® ), and at least a second additional therapeutic agent selected from the group consisting of: HBV virus entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, B HBV antibody, siRNA, miRNA gene therapy agent, sshRNA, KDM5 inhibitor and nucleoprotein modulator (HBV core or capsid protein modulator) targeting the surface antigen of hepatitis virus.

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} (in Thailand car ^®) or lamivudine (epi vir -HBV ^®); 1, 2, or 3 additional therapeutic agents selected from the group consisting of: immunomodulatory agent, TLR modulator, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBV therapeutic vaccine, HBV antibody targeting the surface antigen of hepatitis B virus and HBV antibodies, including bispecific antibodies, and the "antibody-like" therapeutic protein (e.g. DART ^®, Duo ^® body, byte ^®, XmAb ^{®, ®} TANDBERG Ab, Fab derivatives, TCR- or similar antibody), a cycloalkyl pilrin inhibitor, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and stimulators of NOD2; and 1 or 2 additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, HBV antibody targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} (in Thailand car ^®) or lamivudine (epi vir -HBV ^®); 1 or 2 additional therapeutic agents selected from the group consisting of: immunomodulatory agent, TLR modulator, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBV therapeutic vaccine, HBV including HBV antibody targeting the surface antigen of hepatitis B virus antibodies and bispecific antibodies, and "antibody-like" therapeutic protein (e.g. DART ^®, Duo ^® body, byte ^®, XmAb ^{®, ®} TANDBERG Ab, Fab derivatives, TCR- or similar antibody), a cycloalkyl pilrin inhibitor, retinoic acid - stimulators of inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and stimulators of NOD2; and 1 or 2 additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, HBV antibody targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

The first additional therapeutic agents In certain embodiments, the salt of the compound or the acceptable pharmaceutically disclosed herein are selected from the group consisting of: O depot builder (Hepsera ^®), tenofovir builder disoproxil fumarate (irregularities adjuster ^® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ^{entecavir (baraclud ® ), telbivudine} ( ^{Taizeca ®} ) or lamivudine (Epivir-HBV ^® ), and 1, 2, 3, or 4 additional therapeutic agents selected from the group consisting of: an immunomodulatory agent, a TLR7 modulator, a TLR8 modulator, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccine, HBV antibody, including HBV antibodies and bispecific antibodies targeting the surface antigen of hepatitis B virus and the "antibody-like" therapeutic protein (e.g. DART ^®, Duo body ^® , byte ^®, XmAb ^{®, ®} TANDBERG Ab, Fab derivatives, TCR- or similar antibody), a cycloalkyl pilrin inhibitor, retinoic acid-induced stimulator of stimulator of gene 1, RIG-I-like receptor, PD-1 inhibitors, PD- L1 inhibitor, arginase inhibitor, PI3K inhibitor, IDO inhibitor, stimulator of NOD2, HBV virus entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, siRNA, miRNA gene therapy agent, sshRNA, KDM5 inhibitor and nucleoprotein modulator (HBV core) or capsid protein modulators).

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is disclosed in U.S. Publication No. 2010/0143301 (Gilliad Sciences), U.S. Publication No. 2011/0098248 (Gilliad Sciences), U.S. Publication No. 2009/0047249 (Gilliad Sciences) Gilead Sciences), U.S. Patent No. 8722054 (Gilliad Sciences), U.S. Publication No. 2014/0045849 (Jansen), U.S. Publication No. 2014/0073642 (Jansens), WO2014/056953 (Jansen), WO2014/076221 (Jansen) , WO2014/128189 (Jansen), US Publication No. 2014/0350031 (Jansen), WO2014/023813 (Jansen), US Publication No. 2008/0234251 (Array BioPharma), US Publication No. 2008/0306050 (Array BioPharma), USA Publication Nos. 2010/0029585 (VentiRX Pharma), US Publication Nos. 2011/0092485 (VentiRX Pharma), US2011/0118235 (VentiRX Pharma), US Publication Nos. 2012/0082658 (VentiRX Pharma), US Publication Nos. No. 2012/0219615 (VentiRX Pharma), U.S. Publication No. 2014/0066432 (VentiRX Pharma), U.S. Publication No. 2014/0088085 (VentiRX Pharma), U.S. Publication No. 2014/0275167 (Novira Therapeutics) , U.S. Publication No. 2013/0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilliad Sciences), U.S. Publication No. 2014/0030221 (Gilliad Sciences), U.S. Publication No. 2013/0344030 (Gilliad Sciences) ), US Publication Nos. 2013/0344029 (Gilliad Sciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Publication Nos. 2014/0343032 (Roche), WO2014037480 (Roche), US Publications No. 2013/0267517 (Roche), WO2014131847 (Janssen) ), WO2014033176 (Jansen), WO2014033170 (Jansen), WO2014033167 (Jansen), WO2015/059212 (Jansen), WO2015118057 (Jansen), WO2015011281 (Jansen), WO2014184365 (Jansen), WO2014184350 (Jansen), WO2014161888 (Jansen), WO2013096744 (Nobira), US20150225355 (Nobira), US20140178337 (Nobira), US20150315159 (Nobira), US20150197533 (Nobira), US20150274652 (Nobira), US201505259324 (Nobira), US20150132258 (Nobira), US9181288 (Nobira) D), WO2014184350 (Jansen), WO2013144129 (Roche), US20100015178 (Insight), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.) Inc.), U.S. Publication No. 2014/0330015 (Ono Pharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical), U.S. Publication No. 2013/0217880 (Ono Pharmaceutical), WO2016057924 (Genen) Tech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quantech) Ticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Orizon Genomics), and other drugs for treating HBV, and combinations thereof.

In certain embodiments, one or more compounds as disclosed herein (eg, any compound of Formula I) can be administered in any dosage (eg, from 10 mg to 1000 mg of compound) of a compound of Formula (I). (eg, 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. . In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compound as disclosed herein (eg, a compound of Formula I) can be administered in any dosage of the compound (eg, 50 mg of a compound), such that each combination of dosages is specifically and individually listed. to 500 mg) with the agents provided herein.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. . In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or in combination with tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. A compound as disclosed herein (eg, a compound of Formula I) can be administered in any dosage of the compound (eg, 50 mg of a compound), such that each combination of dosages is specifically and individually listed. to 500 mg) with an agent provided herein.

In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) ) in combination with an additional therapeutic agent.

VII. Combination therapy for HCV

In certain embodiments, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human suffering from or at risk of HCV infection in a therapeutically effective amount of one or more (e.g., 1, 2, 3, There is provided a method of treating or preventing HCV infection in said human comprising administering in combination with one or two, or one to three) additional therapeutic agents. In one embodiment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human suffering from or at risk of HCV infection in a therapeutically effective amount of one or more (e.g., 1, 2, 3, There is provided a method of treating HCV infection in said human comprising administering in combination with one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, in a therapeutically effective amount suitable for treating an HCV infection, of one or more additional additional agents. A method of treating HCV infection comprising administering in combination with a therapeutic agent is provided.

In this embodiment, the additional therapeutic agent may be an anti-HCV agent. For example, in some embodiments, the additional therapeutic agent is interferon, ribavirin or analog thereof, HCV NS3 protease inhibitor, HCV NS4 protease inhibitor, HCV NS3/NS4 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, HCV NS5B Nucleoside or nucleotide inhibitors of polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, and pharmacokinetic enhancers, US2010/0310512, US2013/0102525 , and a compound as disclosed in WO2013/185093, or a combination thereof.

In certain embodiments a compound of the present disclosure (eg, a compound of Formula (I)) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HCV. In certain embodiments, the tablet comprises another active ingredient for treating HCV, such as interferon, ribavirin or analog thereof, HCV NS3 protease inhibitor, HCV NS4 protease inhibitor, HCV NS3/NS4 protease inhibitor, alpha-glucosidase 1 inhibitor, Hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, and pharmacokinetic enhancers thereof, or their may contain combinations.

In certain embodiments, such tablets are suitable for once daily administration.

In certain embodiments, the additional therapeutic agent is selected from one or more of the following:

(1) PEGylated rIFN-alpha 2b (PEG-intron), pegylated rIFN-alpha 2a (Pegasis), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Loferon-A), interferon alpha (MOR-) 22, OPC-18, Alphaferon, AlphaNative, Multiferon, Subalin), Interferon Alphacon-1 (Infergen), Interferon Alpha-n1 (Wellferon), Interferon Alpha-n3 (Alferon), Interferon-Beta (Abonex, DL-8234), Interferon-Omega (Omega Durose, Biomed 510), Alvinterferon Alpha-2b (Albuferon), IFN Alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), or bellerophon, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, Infergen, Revif, PEGylated IFN-beta, oral interferon alpha, peron, reaferon, intermax alpha, r-IFN-beta, and infergen plus actimuneribavirin and ribavirin analogs such as lebetol, copegus, VX- 497, and an interferon selected from the group consisting of viramidine (taribavirin);

(2) ribavirin and analogs thereof selected from the group consisting of ribavirin (levetol, copegus), and taribavirin (viramidine);

(3) Compound A.1 (described below), compound A.2 (described below), compound A.3 (described below), ABT-267, compound A.4 (described below), JNJ-47910382 , Daclatasvir (BMS-790052), ABT-267, Samatasvir, MK-8742, MK-8404, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102, A-831 NS5A inhibitor selected from the group consisting of , A-689, AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052;

(4) sofosbuvir (GS-7977), compound A.5 (described below), compound A.6 (described below), ABT-333, compound A.7 (described below), ABT-072, Compound A.8 (described below), tegobuvir (GS-9190), GS-9669, TMC647055, ABT-333, ABT-072, cetrobuvir (ANA-598), IDX-21437, filibuvir (PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127, Valopicitabine (NM-283), PSI-6130 (R1656), PSI-7851, BCX-4678, Nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759, GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837, NS5B polymerase inhibitors selected from the group consisting of GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, BILB-1941, AL-335, AL-516 and ACH-3422;

(5) compound A.9, compound A.10, compound A.11, ABT-450, compound A.12 (described below), simeprevir (TMC-435), boceprevir (SCH-503034), narlaprevir (SCH-900518), baniprevir (MK-7009), MK-5172, danoprevir (ITMN-191), sovaprevir (ACH-1625), neseprevir (ACH-2684), Telaprevir (VX-950), VX-813, VX-500, Faldaprevir (BI-201335), Asunaprevir (BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, protease (NS3, NS3-NS4) inhibitors selected from the group consisting of BILN-2065, and BILN-2061;

(6) an alpha-glucosidase 1 inhibitor selected from the group consisting of celgosivir (MX-3253), miglitol, and UT-231B;

(7) a hepatoprotectant selected from the group consisting of emerica acid (IDN-6556), ME-3738, GS-9450 (LB-84451), silybilin and mitoQ;

(8) a TLR7 agonist selected from the group consisting of imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), and SM-360320;

(9) a cyclophilin inhibitor selected from the group consisting of Devio-025, SCY-635, and NIM811;

(10) an HCV IRES inhibitor selected from the group consisting of MCI-067;

(11) a pharmacokinetic enhancer selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and loxithromycin; and

(12) Thymosin alpha 1 (Zadaxin), Nitazoxanide (Alinia, NTZ), BIVN-401 (Virostat), PYN-17 (Altirex), KPE02003002, Actilon (CPG-10101), GS- 9525, KRN-7000, Shivacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, Tarvacin, EHC-18, VGX-410C, EMZ-702 , AVI 4065, BMS-650032, BMS-791325, babituximab, MDX-1106 (ono-4538), oglupanide, VX-497 (merimepodib) NIM811, benzimidazole derivatives, benzo-1,2 Other anti-HCV agents selected from the group consisting of ,4-thiadiazine derivatives, and phenylalanine derivatives.

Compound A.1 is an inhibitor of HCV NS5A protein and is represented by the following chemical structure:

(See, eg, US Application Publication No. 20100310512 A1).

Compound A.2 is an NS5A inhibitor and is represented by the following chemical structure:

Compound A.3 is an NS5A inhibitor and is represented by the following chemical structure:

Compound A.4 is an NS5A inhibitor and is represented by the following chemical structure:

(See US Application Publication No. 2013/0102525 and its references.)

Compound A.5 is an NS5B island II polymerase inhibitor and is represented by the following chemical structure:

Compound A.6 is a nucleotide inhibitor prodrug designed to inhibit the replication of viral RNA by HCV NS5B polymerase, and is represented by the following chemical structure:

Compound A.7 is an HCV polymerase inhibitor and is represented by the structure:

(See US Application Publication No. 2013/0102525 and references therein).

Compound A.8 is an HCV polymerase inhibitor and is represented by the structure:

(See US Application Publication No. 2013/0102525 and references therein).

Compound A.9 is an HCV protease inhibitor and is represented by the following chemical structure:

Compound A.10 is an HCV protease inhibitor and is represented by the following chemical structure:

Compound A.11 is an HCV protease inhibitor and is represented by the following chemical structure:

Compound A.12 is an HCV protease inhibitor and is represented by the following chemical structure:

(See US Application Publication No. 2013/0102525 and references therein).

In one embodiment, the additional therapeutic agent used in combination with a pharmaceutical composition as described herein is a HCV NS3 protease inhibitor. Non-limiting examples include:

In another embodiment, the additional therapeutic agent used in combination with a pharmaceutical composition as described herein is a cyclophilin inhibitor, including, for example, cyclophilin inhibitors disclosed in WO2013/185093. In addition to those listed above, non-limiting examples include:

and stereoisomers and mixtures of stereoisomers thereof.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, a HCV NS3 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, a HCV NS3/NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS4 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3/NS4 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3 protease inhibitor, a pharmacokinetic enhancer and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS4 protease inhibitor, a pharmacokinetic enhancer and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3/NS4 protease inhibitor, a pharmacokinetic enhancer and an HCV NS5A inhibitor.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is simeprevir, MK-8742, MK-8408, MK-5172, ABT-450, ABT-267, ABT-333, sofosbuvir, Sofosbuvir + ledipasvir, sofosbuvir + GS-5816, sofosbuvir + GS-9857 + ledipasvir, ABT-450 + ABT-267 + ritonavir, ABT-450 + ABT-267 + ribavirin + Ritonavir, ABT-450 + ABT-267 + Ribavirin + ABT-333 + Ritonavir, ABT-530 + ABT-493, MK-8742 + MK-5172, MK-8408 + MK-3682 + MK-5172, MK-8742 + MK-3682 + MK-5172, Daclatasvir, Interferon, PEGylated Interferon, Ribavirin, Samatasvir, MK-3682, ACH-3422, AL-335, IDX-21437, IDX-21459, Te Gobuvir, cetrobuvir, valoficitabine, boceprevir, narlaprevir, baniprevir, danoprevir, sovaprevir, neseprevir, telaprevir, faldaprevir, asunaprevir, ledipasvir, GS-5816, GS-9857, ACH-3102, ACH-3422 + ACH-3102, ACH-3422 + sovaprevir + ACH-3102, asunaprevir, asunaprevir + daclatasvir , AL-516, and petroprevir 1, 2, 3, 4 or more additional therapeutic agents.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with simeprevir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742 or MK-8408. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450, ABT-267, or ABT-333. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with biekirat (a combination of ABT-450, ABT-267, and ritonavir). In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with daclatasvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with harvoni (sofosbuvir+ledipasvir). In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir and GS-5816. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir + GS-9857 + ledipasvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450 + ABT-267 + ribavirin + ritonavir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450+ABT-267+ribavirin+ABT-333+ritonavir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-530 + ABT-493. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8408 + MK-3682 + MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742+MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-3682. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with AL-335. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422 + ACH-3102. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422+sovaprevir+ACH-3102. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with GS-5816. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with GS-9857. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with IDX-21459. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with boceprevir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ledipasvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with AL-516.

In various methods, Compound A.1 is administered in an amount ranging from about 10 mg/day to about 200 mg/day. For example, the amount of compound A.1 is about 30 mg/day, about 45 mg/day, about 60 mg/day, about 90 mg/day, about 120 mg/day, about 135 mg/day, about 150 mg/day per day, about 180 mg/day. In some methods, Compound A.1 is administered at about 90 mg/day. In various methods, Compound A.2 is administered in an amount ranging from about 50 mg/day to about 800 mg/day. For example, the amount of Compound A.2 may be about 100 mg/day, about 200 mg/day, or about 400 mg/day. In some methods, the amount of Compound A.3 is from about 10 mg/day to about 200 mg/day. For example, the amount of Compound A.3 may be about 25 mg/day, about 50 mg/day, about 75 mg/day, or about 100 mg/day.

In various methods, sofosbuvir is administered in an amount ranging from about 10 mg/day to about 1000 mg/day. For example, the amount of sofosbuvir is about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day , about 800 mg/day. In some methods, sofosbuvir is administered at about 400 mg/day.

Also disclosed herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing HCV, and one or more additional compounds for treating HCV provide treatment.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HCV, wherein the compound or a pharmaceutically acceptable salt thereof The salt is administered concurrently, separately or sequentially with one or more additional therapeutic agents for treating HCV.

VIII. Combination Therapy for HIV

In certain embodiments, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human afflicted with or at risk of contracting HIV infection with a therapeutically effective amount of one or more (e.g., 1, 2, 3, There is provided a method of treating or preventing HIV infection in said human comprising administering in combination with one or two, or one to three) additional therapeutic agents. In one embodiment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human suffering from or at risk of contracting HIV infection with a therapeutically effective amount of one or more (e.g., 1, 2, 3, There is provided a method of treating HIV infection in said human comprising administering in combination with one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, in a therapeutically effective amount suitable for treating an HIV infection, of one or more additional A method of treating HIV infection comprising administering in combination with a therapeutic agent is provided. In certain embodiments, the one or more additional therapeutic agents include, for example, 1, 2, 3, 4, 1 or 2, 1-3, or 1-4 additional therapeutic agents.

In this embodiment, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (eg CCR5 inhibitors, gp41 inhibitors (ie fusion inhibitors) and CD4 adhesion inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversal agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators and BRD4 inhibitors), HIV capsid targeting compounds ( "capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 Modulators, Pd-L1 modulators, Toll-like receptor modulators, IL-15 agonists), HIV antibodies, including those targeting HIV gp120 or gp41, bispecific antibodies and “antibody-like” therapeutic proteins (e.g., Dart ®, Duobody®, Bite®, XmAb®, TanAb®, Fab derivative), combination drug for HIV, HIV p17 matrix protein inhibitor, IL-13 antagonist, peptidyl-prolyl cis-trans isomerase A modulator, Protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, HIV-1 virus infectious factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed class kinases -3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain containing protein 1 set Purification, HIV ribonuclease H inhibitor, retrocyclin modulator, CDK-9 inhibitor, dendritic ICAM-3 graving non-integrin 1 inhibitor, HIV GAG protein inhibitor, HIV POL protein inhibitor, complement factor H modulator, ubiquitin ligase inhibitor , deoxycytidine kinase inhibitor, cyclin dependent kinase inhibitor, proprotein convertase PC9 stimulator, ATP dependent RNA helicase DDX3X inhibitor, reverse transcriptase priming complex inhibitor, PI3K inhibitor, WO 2013/006738 (Gilliad Sciences) , US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilliad Sciences), WO 2012/145728 (Gilliad Sciences), WO2012/003497 (Gilliad Sciences), WO2014/100323 (Gilliad Sciences) ), WO2012/145728 (Gilliard Sciences), WO2013/159064 (Gilliad Sciences) and WO 2012/003498 (Gilliad Sciences) and WO 2013/006792 (Pharma Resources). compounds, and other drugs for treating HIV, and combinations thereof. In some embodiments, the additional therapeutic agent is further selected from a Vif dimerization antagonist and an HIV gene therapy.

In certain embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV ratio -catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments a compound of the present disclosure is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet comprises another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide of reverse transcriptase. inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily administration.

In certain embodiments, the additional therapeutic agent is selected from one or more of the following:

(1) ATRIPLA® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), COMPLERA® (EVIPLERA®, rilpivirine + tenofo) vir disoproxil fumarate + emtricitabine), STRIBILD® (elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine), dolutegravir + abacavir alcohol Pate + lamivudine, TRIUMEQ® (dolutegravir + abacavir + lamivudine), lamivudine + nevirapine + zidovudine, dolutegravir + rilpivirine, atazanavir sulfate + cobicistat, darunabi Le + cobicistat, efavirenz + lamivudine + tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate + emtricitabine + cobicistat + elvitegravir, Vacc-4x + romidepsin , darunavir + tenofovir alafenamide hemifumarate + emtricitabine + cobicistat, APH-0812, raltegravir + ramivudine, KALETRA® (ALUVIA®, lopinavir) +ritonavir), atazanavir sulfate + ritonavir, COMBIVIR® (zidovudine+lamivudine, AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate) +lamivudine, ABC+3TC), TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), Truvada® (tenofovir disoproxil fumarate+emtricitabine, TDF+) FTC), a combination drug selected from the group consisting of tenofovir + lamivudine and lamivudine + tenofovir disoproxil fumarate, as well as dolutegravir + rilpivirine hydrochloride, atazanavir + cobicistat, tenofovir Alafenamide hemifumarate + emtricitabine, tenofovir alafenamide + emtricitabine, tenofovir alafenamide hemifumarate + emtricitabine + rilpivirine, tenofovir alafenamide + emtricitabine + Rilpivirine, doravirine + lamivudine + a combination drug selected from tenofovir disoproxil fumarate, doravirine + lamivudine + tenofovir disoproxil;

(2) amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquina an HIV protease inhibitor selected from the group consisting of vir, saquinavir mesylate, tifnavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;

(3) the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapavirine, doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan and AIC-292 HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from;

(4) VIDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, sensabudine, abacavir, abacavir sulfate, Amdoxor, elbucitabine, allovudine, phosphazide, posivudine tidoxil, apricitabine, amdoxor, KP-1461, fosalbudine tidoxil, tenofovir, tenofovir disoproxil, te Nofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir an HIV nucleoside or nucleotide inhibitor of reverse transcriptase selected from the group consisting of vir dipivoxil, and pestinavir;

(5) Curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives , caffeic acid phenethyl ester, caffeic acid phenethyl ester derivative, tyrpostine, tyrphostine derivative, quercetin, quercetin derivative, raltegravir, elvitegravir, dolutegravir and group consisting of cabotegravir an HIV integrase inhibitor selected from, as well as an HIV integrase inhibitor selected from JTK-351;

(6) an HIV non-catalytic site selected from the group consisting of CX-05168, CX-05045 and CX-14442, or an allosteric, integrase inhibitor (NCINI);

(7) an HIV gp41 inhibitor selected from the group consisting of enfuvirtide, cifuvirtide and albuvirtide;

(8) an HIV entry inhibitor selected from the group consisting of cenicriviroc;

(9) an HIV gp120 inhibitor selected from the group consisting of Radha-108 (Receptol) and BMS-663068;

(10) Aflaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), TBR-220 (TAK-220), nifeviroc (TD-0232), TD-0680 , and a CCR5 inhibitor selected from the group consisting of vMIP (Haimifu);

(11) a CD4 adhesion inhibitor selected from the group consisting of ivalizumab;

(12) a CXCR4 inhibitor selected from the group consisting of plerixapor, ALT-1188, vMIP and hymifu;

(13) a pharmacokinetic enhancer selected from the group consisting of cobicistat and ritonavir;

(14) dermavir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon Gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivatives mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymeric polyethyleneimine (PEI), gepon, VGV-1, MOR-22, BMS-936559, Toll-like receptor modulators (TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), lintatolimod and IR an immune-based therapy selected from the group consisting of -103;

(15) peptide vaccine, recombinant subunit protein vaccine, live vector vaccine, DNA vaccine, virus-like particle vaccine (pseudovirion vaccine), CD4-derived peptide vaccine, vaccine combination, rgp120 (AIDSVAX), Alvac HIV (vCP1521)/AIDSbox B/E (gp120) (RV144), Remune, ITV-1, Contrevir, Ad5-Enva-48, DCBox-001 (CDX-2401), PEP-6409, Vacc- 4x, Vacc-C5, VAC-3S, Multiclad DNA Recombinant Adenovirus-5 (rAd5), Penvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi Vaccine, AVX -201, HIV-LAMP-box, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccine, tartimmune, GTU-multiHIV (FIT-06), AGS-004, gp140[delta]V2 .TV1+ MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, hivax, hivax-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Bishrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4 -env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, Prevaxstart, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, Adbox, MYM-V201, MVA HIV vaccine selected from the group consisting of -CMDR, ETV-01 and DNA-Ad5 gag/pol/nef/nev (HVTN505), as well as monomeric gp120 HIV-1 subtype C vaccine (Novartis), HIV- from Trimix-mRNA, MVATG-17401, ETV-01, CDX-1401, and rcAd26.MOS1.HIV-Env selected HIV vaccines;

(16) HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins (such as Dart®, Duobody®, Bite®, XmAb®, TanAb®, Fab derivatives), such as BMS-936559, TMB-360 , and with babituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8 and VRC07 targeting HIV gp120 or gp41 selected from the group consisting of, as well as HIV antibodies such as VRC-07-523;

(17) histone deacetylase inhibitors such as romidepsin, vorinostat, panobinostat; proteasome inhibitors such as Velcade; Protein kinase C (PKC) activators such as indolactam, prostratin, ingenol B and DAG-lactone, ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitor, IL-15, JQ1, disulfram, and amphoteric a latent reversal agent selected from the group consisting of tericin B;

(18) an HIV nucleocapsid p7 (NCp7) inhibitor selected from the group consisting of azodicarbonamides;

(19) an HIV maturation inhibitor selected from the group consisting of BMS-955176 and GSK-2838232;

(20) idelarisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigocertib, rigocertib sodium, EN-3342, TGR-1202, alfelisib, Duveli 10, UCB-5857, Taselisib, XL-765, Gedatolisib, VS-5584, Copanlisib, CAI Orotate, Perifosin, RG-7666, GSK-2636771, DS-7423, Panulisib, GSK- 2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, fuquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117 , a PI3K inhibitor selected from the group consisting of SF-1126, RV-1729, Sonolisib, LY-3023414, SAR-260301 and CLR-1401;

(21) WO 2004/096286 (Gilliad Sciences), WO 2006/110157 (Gilliad Sciences), WO 2006/015261 (Gilliad Sciences), WO 2013/006738 (Gilliad Sciences), US 2013/ 0165489 (University of Pennsylvania), US20140221380 (Tobacco Japan), US20140221378 (Tobacco Japan), WO 2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013 /091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilliad Sciences), WO 2012/145728 (Gilliad Sciences), WO2012/003497 (Gilliad Sciences), WO2014/100323 (Gilliad Sciences), compounds disclosed in WO2012/145728 (Gilliad Sciences), WO2013/159064 (Gilliad Sciences) and WO 2012/003498 (Gilliad Sciences); and

(22) Vanlec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02, methenkephaline, PGN-007, acemannan , Gamimmune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR- 576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, Block-Aid, ABX-464, SCY-635, naltrexone and PA-1050040 (PA-040) other drugs to treat; and other drugs for treating HIV selected from AAV-eCD4-Ig gene therapy, TEV-90110, TEV-90112, TEV-90111, TEV-90113, Diperipron, and HS-10234.

In certain embodiments, the additional therapeutic agent is a compound disclosed in US 2014-0221356 (Gilliad Sciences, Inc.), e.g., (2R,5S,13aR)-N-(2,4-difluorobenzyl)- 8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5] Pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7 ,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1 -b][1,3]oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo- 1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide; (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a -octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7, 9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1' ,2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, and (1R,4S,12aR)-N-(2,4-difluoro benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1 ',2'-d]pyrazine-9-carboxamide, a compound disclosed in US2015-0018298 (Gilliad Sciences, Inc.) and US2015-0018359 (Gilliad Sciences, Inc.).

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 1, 2, 3, 4 or more additional therapeutic agents. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The 1, 2, 3, 4 or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or may be selected from different classes of therapeutic agents.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitory compound. In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibitory compound are combined In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer are combined In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents selected from HIV nucleoside inhibitors of reverse transcriptase, integrase inhibitors, and pharmacokinetic enhancers. In another embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleosides or nucleotide inhibitors of reverse transcriptase.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is Triumec® (dolutegravir+abacavir+lamivudine), dolutegravir+abacavir sulfate+lamivudine, raltegravir , Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), maraviroc, enfuvirtide, Epsicom® (Rivexa®, abacavir sulfate + ramivudine, ABC+3TC), Trizivir® (abacavir sulfate + zidovudine + ramivudine, ABC + AZT + 3TC), adefovir, adefovir dipivoxil, stribuil® (elvitegravir + cobicistat + tenofovir disoproxil puma) Late + Emtricitabine), Rilpivirine, Rilpivirine Hydrochloride, Complera® (Ebiflara®, Rilpivirine + Tenofovir Disoproxil Fumarate + Emtricitabine), Cobicistat, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, aluvia® (kaletra®, lopinavir+ ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir, darunavir, lamivudine, prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, combivir® ( zidovudine + lamivudine, AZT + 3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevir Raffin, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tifnavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, Lamivudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate, phosphazide, lamivudine + nevirapine + zidovudine, abacavir, abacavir sulfate, tenofovir, te 1, 2, 3 or 4 selected from nofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate; is combined with more additional therapeutic agents. In certain embodiments, the 1, 2, 3, 4 or more additional therapeutic agents are raltegravir + lamivudine, atazanavir sulfate + cobicistat, atazanavir + cobicistat, darunavir + further selected from cobicistat, darunavir + cobicistat, atazanavir sulfate + cobicistat, atazanavir + cobicistat.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is Triumec® (dolutegravir+abacavir+lamivudine), dolutegravir+abacavir sulfate+lamivudine, raltegravir , Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), maraviroc, enfuvirtide, Epsicom® (Rivexa®, abacavir sulfate + ramivudine, ABC+3TC), Trizivir® (abacavir sulfate + zidovudine + ramivudine, ABC + AZT + 3TC), adefovir, adefovir dipivoxil, stribuil® (elvitegravir + cobicistat + tenofovir disoproxil puma) Late + Emtricitabine), Rilpivirine, Rilpivirine Hydrochloride, Complera® (Ebiflara®, Rilpivirine + Tenofovir Disoproxil Fumarate + Emtricitabine), Cobicistat, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, aluvia® (kaletra®, lopinavir+ ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir, darunavir, lamivudine, prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, combivir® ( zidovudine + lamivudine, AZT + 3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevir Raffin, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tifnavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, Lamivudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate, phosphazide, lamivudine + nevirapine + zidovudine, (2R,5S,13aR)-N-(2, 4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1' , 2': 4,5] pyrazino [2,1-b] [1,3] oxazepine-10- Carboxamide, (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13 ,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (1S ,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro- 1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide, (1R,4S,12aR)-7-hydroxy-6,8-dioxo -N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a: 1',2'-d]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl) -2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazepine-10-carboxamide, and (1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2, 3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide Abacavir, abacavir 1, 2, 3 or 4 selected from sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate; or in combination with more additional therapeutic agents.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemi in combination with fumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir ala in combination with phenamide hemifumarate.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir di in combination with soproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of: emtricitabine and lamivudine.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent emtricitabine.

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 in combination with mg emtricitabine. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg M. combined with tricitabine. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg M. combined with tricitabine. A compound of the present disclosure (eg, a compound of Formula (I)) can be administered in any dosage of a compound (eg, 1 of a compound), such that each combination of dosages is specifically and individually listed. mg to 500 mg).

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 in combination with mg emtricitabine. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, comprises 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg M. combined with tricitabine. A compound of the present disclosure (eg, a compound of Formula (I)) can be administered in any dosage of a compound (eg, 50 of a compound), such that each combination of dosages is specifically and individually listed. mg to 500 mg). A compound of the present disclosure (eg, a compound of Formula (I)) can be administered in any dosage of a compound (eg, a compound of formula (I)), such that each combination of dosages is specifically and individually listed. 1 mg to about 150 mg) with an agent provided herein.

In certain embodiments a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is (2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo- 2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1, 3]oxazepine-10-carboxamide, (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4, 5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10 -carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide, (1R,4S,12aR)-7-hydroxy -6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido [1,2-a:1 ',2'-d]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4, 6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2 ,1-b][1,3]oxazepine-10-carboxamide, or (1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8- dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-car combined with boxamide.

Also provided herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing HIV, and one or more additional compounds for treating HIV provide treatment.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV, wherein the compound or a pharmaceutically acceptable salt thereof The salt is administered simultaneously, separately or sequentially with the one or more additional therapeutic agents for treating HIV.

In certain embodiments, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human in a therapeutically effective amount of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3). species) is provided in combination with an additional therapeutic agent for treating a hyperproliferative disorder, such as cancer, in a human. In one embodiment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a human in a therapeutically effective amount of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3). species) is provided in combination with an additional therapeutic agent for treating a hyperproliferative disorder, such as cancer, in a human.

IX. Combination Therapy for Cancer

In certain embodiments, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, suitable for treating a hyperproliferative disorder, such as cancer, to a patient in need thereof. Provided is a method of treating a hyperproliferative disorder, such as cancer, comprising administering in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In the above embodiment, the additional therapeutic agent may be an anti-cancer agent. For example, in some embodiments, the additional therapeutic agent is a chemotherapeutic agent, immunotherapeutic agent, radiotherapeutic agent, anti-neoplastic agent, anti-hormonal agent, anti-angiogenic agent, anti-fibrotic agent, therapeutic antibody, tyrosine kinase inhibitor, JAK inhibitors, hedgehog inhibitors, HDAC inhibitors, discoidin domain receptor (DDR) inhibitors, MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR inhibitors, AKT inhibitors, mitogen or extracellular regulatory kinases ( MEK) inhibitor, Raf kinase (rafk) blocker, CDK inhibitor, JNK inhibitor, MAPK inhibitor, Raf inhibitor, ROCK inhibitor, Tie2 inhibitor, myo-inositol signaling inhibitor, phospholipase C blocker, anti-CD19 antibody, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, cancer vaccines based on the genetic makeup of an individual patient's tumor, IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCR inhibitors, agents that inhibit the RAS/RAF/ERK pathway, protein kinase C (PKC) modulators, growth factor receptors such as epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret, Modulator of vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms) ), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB, and TrkC), ephrin (eph) receptor, and RET proto-oncogenes, cSrc, Lck, Fyn, Yes, cAbl , modulators of tyrosine kinases, including FAK (locally attached kinase) and Bcr-Abl, modulators of PKB family kinases, modulators of TGF beta receptor kinases, farnesyltransferases, geranyl-geranyl transferases, and inhibitors of CAAX proteases. inhibitors of Ras oncogenes, including antisense oligonucleotides, ribozymes, Bcl-2 family protein inhibitors, proteasome inhibitors, heat shock protein HSP90 inhibitors, combination drugs and immunotherapy, and other for treating hyperproliferative disorders such as cancer drugs, and combinations thereof.

In certain embodiments a compound of the present disclosure is formulated as a tablet, which may optionally contain one or more other compounds useful for treating cancer. In certain embodiments, the tablet contains another active ingredient for treating cancer, such as a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an antineoplastic agent, an antifibrotic agent, an antihormonal agent, an antiangiogenic agent, a tyrosine kinase inhibitor , JAK inhibitors, hedgehog inhibitors, HDAC inhibitors, discoidin domain receptor (DDR) inhibitors, MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR inhibitors, AKT inhibitors, mitogen or extracellular regulation kinase (MEK) inhibitors, Raf kinase (rafk) blockers, CDK inhibitors, JNK inhibitors, MAPK inhibitors, Raf inhibitors, ROCK inhibitors, Tie2 inhibitors, myo-inositol signaling inhibitors, phospholipase C blockers, IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCR inhibitors, agents that inhibit the RAS/RAF/ERK pathway, protein kinase C (PKC) modulators, growth factor receptors such as epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret, Modulator of vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms) ), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB, and TrkC), ephrin (eph) receptor, and RET proto-oncogenes, cSrc, Lck, Fyn, Yes, cAbl , modulators of tyrosine kinases including FAK (localized adhesion kinase) and Bcr-Abl, modulators of PKB family kinases, modulators of TGF beta receptor kinases, farnesyltransferases, geranyl-geranyl transferases, and inhibitors of CAAX proteases. inhibitors of Ras oncogenes, including antisense oligonucleotides, ribozymes, Bcl-2 family protein inhibitors, proteasome inhibitors, heat shock protein HSP90 inhibitors, combination drugs and immunotherapy, and other for treating hyperproliferative disorders such as cancer drugs, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily administration. In certain embodiments, the additional therapeutic agent is selected from one or more of the following:

(1) a chemotherapeutic agent selected from the group consisting of: antimetabolites/anticancer agents such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); Purine analogs, folate antagonists and related inhibitors, antiproliferative/antimitotic agents such as natural products such as vinca alkaloids (vinblastine, vincristine) and microtubules such as taxanes (paclitaxel, docetaxel), vinblastine, no codazole, epothilon and nabelbine, epipodophyllotoxin (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxane, dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin) and mitomycin; enzymes (L-asparaginase that systemically metabolizes L-asparagine and renders the cell incapable of synthesizing its own asparagine); antiplatelet agents; Antiproliferative/antimitotic alkylating agents such as nitrogen mustard cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin, traze Ness-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxaliplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogues (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (eg, tissue plasminogen activators, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (bleveldin); immunosuppressive tacrolimus, sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides; cell cycle inhibitors and differentiation inducers (tretinoin); Inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone) , dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone); growth factor signaling kinase inhibitors; Dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators , chromatin, alkylating agents such as thiotepa and cyclophosphamides (citoxane, endoxane, endoxana, cyclostine), alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumin and buckwheat melamine, including alpretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemilolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CBI-TMI); eleuterobin; pancratistatin; sarcodictine; spongestatin; nitrogen mustards such as chlorambucil, chlornaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembikin, phenesterine, pred nimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, potemustine, lomustine, nimustine, ranimustine; Antibiotics such as enedyin antibiotics (eg, calicheamicin, particularly calicheamicin gammaII and calicheamicin phiI1, for example Agnew, Chem. Intl. Ed. Engl, 33:183-186 ( 1994)]); dynemycins, including dynemycin A; bisphosphonates such as clodronate; esperamicin; as well as neocarzinostatin chromophore and related pigment protein enediin antibiotic chromophore), aclasinomycin, actinomycin, automycin, azaserine, bleomycin, cactinomycin, carabicin, carninomycin, carcinomycin pilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin, including pegylated liposomal doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamicin, olibomycin , peplomycin, portpyromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubersidin, ubenimex, ginostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; anti-adrenal agents such as aminoglutethimide, mitotan, trillostane; folic acid supplements such as prolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; enyluracil; amsacrine; hestrabucil; bisantrene; edatraxate; depopamine; demecholcin; diagequon; Lformtin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; Ronidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; fur damol; nitracrine; pentostatin; phenamet; pyrarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK(r); Lazoxic acid; lyzoxine; sijopiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-triquorotriemylamine; trichothecenes (especially T-2 toxins, veracurin A, loridine A and anguidin); urethanes; vindesine; dacarbazine; mannomustine; mitobronitol ; mitolactol; fipobroman; psitocin; arabinoside ("Ara-C"); cyclophosphamide; thiofeta; taxoid, paclitaxel (taxol) and docetaxel (taxotere); chlorambucil; gemcitabine (Gemzar); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; platinum; ifosfamide; mitoxantrone; vincristine; vinorelbine (nabelbine); novantron; teni Forside; edatrexate; daunomycin; aminopterin; xelloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine and folpyri (fluorouracil, leucovorin and irinotecan);

(2) an anti-hormonal agent selected from the group consisting of: for example tamoxifen (including nolvadex), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and toremifene antiestrogens and selective estrogen receptor modulators (SERMs) including; Inhibitors of the enzyme aromatase that regulate estrogen production in the adrenal glands, such as for example 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozol , letrozole and anastrozole, and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin;

(3) an antiangiogenic agent selected from the group consisting of: retinoid acid and its derivatives, 2-methoxyestradiol, angiostatin, endostatin, suramin, squalamine, tissue inhibitor of metalloproteinase-1, metal tissue inhibitor of loproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupane) ), sulfated chitin derivatives (generally prepared from crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporin, matrix metabolism modulators such as proline analogs ((1-azetidine) -2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl -5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagiline, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, disodium robenzart, n-2-carboxyphenyl-4-chloroanthranilate disodium or "CCA", thalidomide; angiogenesis inhibitory steroids, cargboxinaminolmidazole; metalloproteinase inhibitors such as BB94, antibodies, preferably are monoclonal antibodies to the following angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isotype, VEGF-C, HGF/SF, Ang-1/Ang-2 and Ferrara N. and Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364;

(4) an antifibrotic agent selected from the group consisting of beta-aminopropyrionitrile (BAPN), a primary amine that reacts with the carbonyl group of the active site of lysyl oxidase, more particularly by resonance after binding with the carbonyl those that produce products that are stabilized, such as the following primary amines: emilenemamine, hydrazine, phenylhydrazine and its derivatives, semicarbazide and urea derivatives, aminonitriles such as beta-aminopropionitrile (BAPN) or 2- Nitroethylamine, unsaturated or saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine, selenohomocysteine lactone , copper chelating agents, compounds that block aldehyde derivatives resulting from the oxidative deamination of lysyl and hydroxylysyl residues by indirect inhibitors such as lysyl oxidase, such as thiolamines, especially D-penicillamine or analogs thereof, such as 2-Amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3- Methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamido ethyl-2-acetamidoethanethiol sulfanate, sodium-4-mercaptobutanesulfinate trihydrate, US Pat. No. 4,965,288, US Pat. No. 4,997,854, US Pat. No. 4,943,593, US Pat. No. 5,021,456; US Pat. No. 5,5059,714; US Patent No. 5,120,764; US Patent No. 5,182,297; compounds disclosed in U.S. Patent No. 5,252,608 and U.S. Patent Application No. 2004/0248871;

(5) a therapeutic antibody selected from the group consisting of: abagobumab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arsitumomab, babituximab, bec Tumomab, bevacizumab, vibatuzumab, blinatumomab, brentuximab, cantuzumab, katumaxomab, cetuximab, situtuzumab, drinking watertumumab, civatuzumab, conatumumab, daratu mumab, drogitumab, duligotumab, ducigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, encituximab, ertumaxumab, etaracizumab, parietuzumab , piclatuzumab, pigitumumab, flanbotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igobumab, imgatuzumab, indatuximab, ino tuzumab, intetumumab, ipilimumab, iratumumab, rabetuzumab, lexatumumab, lintuzumab, lorbotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumumab, mituzumab Momap, moxetumab, narnatumab, naftumomab, nesitumumab, nimotuzumab, nofetumomab, okaratuzumab, ofatumumab, olalatumab, onartuzumab, ofortuzumab, oregobomab , panitumumab, parsatuzumab, patritumab, femtumomab, pertuzumab, pintumomab, pritumumab, lakotumomab, radretumab, rilotumumab, rituximab, lovatumumab, satumomab , cibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab , ublituximab, veltuzumab, borsetuzumab, botumumab, zalutumumab, alemtuzumab, veltuzumab, apolizumab, bevacizumab, epratuzumab, tositumomab, galliximab, ibri Tumomab, Lumiliximab, Milatuzumab, Obinutuzumab, Ofatumumab, CC49 and 3F8, wherein the antibody is further directed to a radioisotope particle such as Indium In 111, Yttrium Y 90, Iodine I-131 may be labeled or combined with them;

(6) a JAK inhibitor selected from the group consisting of: ruxolitinib, pedratinib, tofacitinib, baricitinib, restaurtinib, paclitinib, momelotinib, XL019, AZD1480, INCB039110, LY2784544, BMS911543, and NS018;

(7) a hedgehog inhibitor selected from the group consisting of: saridegib;

(8) histone deacetylase (HDAC) inhibitors selected from the group consisting of: prasinostat, romidepsin, vorinostat and panobinostat;

(9) a tyrosine kinase inhibitor selected from the group consisting of restautinib, gefitinib, erlotinib and sunitinib;

(10) a discoidin domain receptor (DDR) inhibitor selected from the group consisting of: inhibitors disclosed in US2009/0142345, US2011/0287011, WO2013/027802, WO2013/034933, and US Provisional Application No. 61/705,044;

(11) MMP9 inhibitors selected from the group consisting of: marimastat (BB-2516), cipemastat (Ro 32-3555), and the inhibitors described in WO2012/027721;

(12) a LOXL inhibitor selected from the group consisting of: the antibody described in WO2009/017833, the antibody described in WO2009/017833, WO2009/035791 and WO/2011/097513;

(13) ASK1 inhibitors selected from the group consisting of: the compounds described in WO2011/008709 and WO/2013/112741;

(14) a PI3K inhibitor selected from the group consisting of: U.S. Patent No. 7,932,260, U.S. Provisional Application No. 61/543,176; 61/581,528; 61/745,429; 61/745,437; and compounds described in 61/835,333, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, Duvelisib, IPI-443, GSK2636771, BAY 10824391, TGX221, RG-7666, CUDC-907, PQR-309, DS-7423, Panulisib, AZD-8186, CLR-457, Pictilisib, Neratinib, Rigocertib, Rigocertib Sodium, EN-3342, UCB-5857, Taselisib, INCB-040093, Pilaralisib, BAY-1082439, Fuquitinib Mesylate, XL-765, Gedatolisib, VS-5584, Copanlisib, CAI Orotate, Alfelisib, Buffa Llicip, BAY 80-6946, BYL719, PX-866, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, RP-6530, AS252424, LY294002, TG100115, LY294002, BEZ235, XL147 (SAR245408), SAR -245409, GDC-0941, BKM120, CH5132799, XL756, MLN-1117, SF-1126, RV-1729, Sonolisip, GDC-0980, CLR-1401, perifosine and wortmannin;

(15) a BTK inhibitor selected from the group consisting of: ibrutinib, HM71224, ono-4059 and CC-292;

(16) a SYK inhibitor selected from the group consisting of: tamatinib (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205 AA, R112, R343, and described in US Pat. No. 8,450,321 compound;

(17) an mTOR inhibitor selected from the group consisting of: temsirolimus, everolimus, ridaforolimus, deforolimus, OSI-027, AZD2014, CC-223, RAD001, LY294002, BEZ235, rapamycin, Ku- 0063794, and PP242;

(18) an AKT inhibitor selected from the group consisting of: perifosine, MK-2206, GDC-0068 and GSK795;

(19) a MEK inhibitor selected from the group consisting of: trametinib, selumetinib, cobimetinib, MEK162, PD-325901, PD-035901, AZD6244, and CI-1040;

(20) a CDK inhibitor selected from the group consisting of: AT-7519, albosideb, palbociclib and SNS-032;

(21) a JNK inhibitor selected from the group consisting of: CC-401;

(22) a MAPK inhibitor selected from the group consisting of: VX-702, SB203580 and SB202190;

(23) a Raf inhibitor selected from the group consisting of: PLX4720;

(24) a ROCK inhibitor selected from the group consisting of: Rho-15;

(25) a Tie2 inhibitor selected from the group consisting of: AMG-Tie2-1;

(26) Myo-inositol signaling inhibitors, such as those described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London. polipase C blockers and myoinositol analogs;

(27) Bcl-2 family protein inhibitors selected from the group consisting of: ABT-263, ABT-199 and ABT-737;

(28) an IKK inhibitor selected from the group consisting of: BMS-345541;

(29) a proteasome inhibitor selected from the group consisting of: bortezomib;

(30) a protein kinase C (PKC) inhibitor selected from the group consisting of: bryostatin 1 and enzastaurine;

(31) a heat shock protein HSP90 inhibitor selected from the group consisting of: geldanamycin;

(32) a combination drug selected from the group consisting of: FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, rituximab), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP ( cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) , ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil and prednisolone), and R MCP (R MCP); and

(33) aldesleukin, albocidib, CHIR-12.12, ha20, tiuxetane, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, autologous human tumor-derived HSPPC-96, GTOP -99 (MyVax®), antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, beta aletin, arsenic trioxide, amifostine, aminocamptothecin, lenalidomide , caspofungin, clofarabine, ixabepilone, cladribine, chlorambucil, curcumin, vinorelbine, tipifarnib, tanespimycin, sildenafil citrate, denileukin diftitox, simvastatin, epoetin alfa, Fenretinide, filgrastim, mesna, mitoxantrone, lenalidomide, fludarabine, mycophenolate mofetil, nelarabine, octreotide, oxaliplatin, pegfilgrastim, recombinant interleukin-12, recombinant a cancer selected from the group consisting of interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, sargramostim, lymphokine-activated killer cells, omega-3 fatty acids, recombinant interferon alpha, therapeutic allogeneic lymphocytes and cyclosporine analogs other drugs to treat

In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is ibrutinib, aldesleukin, albocidib, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, ami Postine trihydrate, aminocamptothecin, arsenic trioxide, beta aletine, ABT-263, ABT-199, ABT-737, BMS-345541, bortezomib, bryostatin 1, busulfan, carboplatin, campat- 1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, cladribine (leustarin), chlorambucil (leukeran), curcumin, cyclosporine, cyclophosphamide (citoxane, endoxane, endoxana, cyclostine), denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, doxorubicin (Adriamycin®, adriblastin), doxorubicin hydrochloride, enzastaurine, epoetin alfa, etoposide, everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, flavopyridol, fludarabine (fludara), geldanamycin (17 AAG), Ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide (Revlimid®), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexapine gadolinium, myco phenolate mofetil, nelarabine, oblimersen obatoclax, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nifent), Perifosine, Prednisolone, Prednisone, Celicillib, Recombinant Interferon Alpha, Recombinant Interleukin-12, Recombinant Interleukin-11, Recombinant Flt3 Ligand, Recombinant Human Thrombopoietin, Rituximab, Sargramostim , sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine , vincristine sulfate, vinorelbine ditartrate, vorinostat (SAHA), vorinostat, FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), HyperCVAD (hyperfractionation) Cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R MCP (R MCP) 1, 2, 3, 4 or more additional therapeutic agents.

Any of the methods of treatment provided can be used to treat various stages of cancer. By way of example, and not limitation, cancer staging includes, but is not limited to, early, advanced, locally advanced, remission, refractory, relapse after remission, and progressive.

In addition, the subject may be a human receiving one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof. Accordingly, the one or more anticancer agents may be administered prior to, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof.

The curative treatment may be supplemented with, or combined with, any of the aforementioned therapies in conjunction with stem cell transplantation or treatment. One example of a modified approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotopic particles such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapy include, but are not limited to, iodine-131 tositumomab (Bexxar®), yttrium-90 ibritumomab tiuxetane (Zevalin®), Bexxar® plus CHOP it doesn't happen

Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, stem cell infusion, stem cell assisted bone marrow resection, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, pharmacological studies, low-LET cobalt-60 gamma-ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyelectomy allogeneic hematopoietic stem cell transplantation.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, and one or more additional therapeutic agents for treating cancer. to provide.

Also provided herein is a compound of the present disclosure (eg, a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, wherein the compound or a pharmaceutically acceptable salt thereof comprises: The one or more additional therapeutic agents for treating cancer are administered simultaneously, separately or sequentially.

X. Kit

The present disclosure provides kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. The kit further comprises instructions for use, eg, for use in modulating a Toll-like receptor (eg, TLR8), such as for use in treating a disease, disorder, or condition. can do. In certain embodiments, the use is for treating HIV, HBV, or HCV infection. In certain embodiments, the use is for treating HBV infection. Instructions for use are generally written instructions, but electronic storage media containing the instructions (eg, magnetic diskettes or optical disks) are also acceptable.

The present disclosure also provides a pharmaceutical kit comprising one or more containers comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Optionally, a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of a pharmaceutical may be associated with such container(s), reflecting approval by the agency for manufacture, use or sale for human administration. . Each component (if more than one component is present) may be packaged in separate containers, or some components may be combined in one container if cross-reactivity and shelf life permit. Kits may be presented in unit dosage form, in bulk packages (eg, multi-dose packages) or in sub-unit doses. Kits may also include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in pharmacies (eg, hospital pharmacies and compounding pharmacies).

XI. compound preparation

Also provided is an article of manufacture comprising a unit dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in a package suitable for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, rulers, flexible packaging, and the like. The article of manufacture may further be sterile and/or hermetically sealed.

Embodiments also relate to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

Many general references are available that provide commonly known chemical synthesis schemes and conditions useful for synthesizing the disclosed compounds (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 ^th edition, Wiley-Interscience, 2013].

The compounds as described herein can be purified by any means known in the art including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. can Any suitable stationary phase may be used, including normal and reverse phases as well as ionic resins. Most typically, the disclosed compounds are purified via silica gel and/or alumina chromatography. See, eg, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969].

During any process for the preparation of a subject compound, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecules involved. This can be accomplished by means of conventional protecting groups as described in standard works, such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4 ^{th ed., Wiley, New York 2006.} The protecting group may be removed in a convenient subsequent step using methods known from the art.

XII. Example

Exemplary chemicals useful in the methods of the embodiments will now be described with reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. The skilled artisan will recognize that, to obtain the various compounds herein, suitable selection of starting materials will ultimately result in transfer of the desired substituents through the schemes, with or without protection, as appropriate, to yield the desired product. Alternatively, it may ultimately be necessary or desirable to use, in place of the desired substituent, a suitable group that may be passed through the scheme and may be appropriately replaced with the desired substituent. Moreover, those skilled in the art will recognize that the transformations shown in the schemes below can be performed in any order compatible with the functional groups of the particular pendant groups. Each reaction shown in the scheme is preferably carried out at about 0° C. to the reflux temperature of the organic solvent used. Unless otherwise specified, a variable is as defined above with respect to formula I or J.

Representative syntheses of the compounds of the present disclosure are described in the following schemes and specific examples below.

Scheme 1 shows a representative synthesis of the compounds of an embodiment. The methodology is compatible with a wide variety of functional groups.

In Scheme 1, a compound of formula A1 in a suitable solvent (such as tetrahydrofuran) and (R)-N-(2-amino-2-methylhexyl)acetamide wherein R ³ and Q are as defined herein or , or R ³ and a suitably protected derivative of Q) are treated with N,N-diisopropylethylamine at about 80° C. to form the compound of formula A2. Treatment of a compound of formula A2 in 2-methyl-tetrahydrofuran with potassium carbonate followed by 2,4-dimethoxybenzylamine forms a compound of formula A3. The compound of formula A3 is then treated with trifluoroacetic acid in a solvent (such as dichloromethane) to form the compound of formula A4.

Scheme 2 shows a representative synthesis of the compounds of an embodiment. The methodology is compatible with a wide variety of functional groups.

A compound of formula B1, wherein Q and R ³ are as defined herein, or a suitably protected derivative of Q, is converted to a compound of formula B2 under suitable reaction conditions. For example, contacting a compound of formula B1 with chloroformamidine hydrochloride under suitable conditions gives B2. Hydroxyl group is, before contact with the R ^B -NH _2, for example, be further modified in any suitable leaving group, for example, by introducing a tosylate. Further, the switch groups -OH suitable reagent, such as chloro group through the use of POCl ₃ and can be in contact with more R ^B -NH ₂ in. Alternatively, R ^B is -NH ₂ under suitable conditions, a suitable coupling agent, for example, may be directly coupled to the ring B2 in the presence of BOP reagent.

Specific embodiments of formula A1 or B1 are described in the present application and additionally in references such as WO2012/156498, WO2012/136834, WO2014/056953, WO2014/076221, WO2015/014815, WO2014/128189, WO2013/117615 and WO2014/023813. can be found in Intermediates corresponding to A1 or analogs thereof (including compounds other than those of formula I) are prepared according to these references and can be used to prepare compounds of the present disclosure.

Except as otherwise indicated, the methods and techniques of embodiments of the present invention are generally described in conventional methods as well known in the art and described in various general and more specific references cited and discussed throughout this specification. performed according to See, eg, Loudon, Organic Chemistry, 5 ^th edition, New York: Oxford University Press, 2009; Refer to Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013]: Smith, March's Advanced Organic Chemistry.

The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It is understood that the individual steps described herein may be combined. It is also understood that separate batches of compounds may be combined and then passed to subsequent synthetic steps.

In the following description of examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice the specific embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description, therefore, is not intended to limit the scope of the present disclosure.

Although the stereochemistry of the enantiomer or diastereomer is not determined in all cases, the methods of the invention generally provide the particular enantiomer or diastereomer as the desired product. When the stereochemistry of a particular stereocenter of an enantiomer or diastereomer has not been determined, a compound may undergo any stereochemistry at that particular stereocenter, even if the compound is substantially enantiomerically or diastereomerically pure. It is drawn without presenting it.

Example 1

Synthesis of (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1a). (R)-(-)-2-phenylglycinol (23.6 g, 172 mmol, supplied by Sigma-Aldrich, 99%) in 2,2,2-trifluoroethanol (500 mL) ee) and molecular sieve (86 g) was added ethyl pyruvate (19.2 mL, 172 mmol, supplied by Sigma Aldrich) and the mixture was heated to reflux. After 24 h, the reaction was cooled to room temperature, filtered through celite, washed with EtOAc and concentrated in vacuo. The residue was subjected to silica gel chromatography with ELSD eluting with hexanes-EtOAc to give 1a. LC/MS (ESI) calculated for _{C 11} H ₁₂ NO ₂ : m/z 190.08, found 189.92 [M+H] ⁺ ; t _R = 0.88 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.45 - 7.38 (m, 2H), 7.38 - 7.32 (m, 3H), 4.85 (ddd, J = 10.9, 4.6, 2.4 Hz, 1H), 4.57 (dd, J = 11.6, 4.5 Hz, 1H), 4.26 (dd, J = 11.6, 10.9 Hz, 1H), 2.41 (d, J = 2.4 Hz, 3H).

Synthesis of (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one (1b). To compound la (14.84 g, 78.43 mmol) in THF (500 mL) at -78°C under argon was added boron trifluoride diethyl etherate (20.5 mL, 161.11 mmol) over 30 min. After 90 min, n-butylmagnesium chloride solution (83.0 mL, 166 mmol, 2.0 M in THF) was added over 30 min. After 2 h, the reaction was warmed to room temperature _{and quenched with saturated NH 4} Cl _(aq) (300 mL). The mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL×3). The organic extracts were washed with water (500 mL×3), brine (300 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DCM (150 mL), heated and the insoluble material removed by filtration. The filtrate was concentrated in vacuo and the residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give compound 1b. LC/MS (ESI) calculated for _{C 15} H ₂₂ NO ₂ : m/z 248.16, found 248.02 [M+H] ⁺ ; t _R = 1.07 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.51 - 7.28 (m, 5H), 4.44 - 4.31 (m, 2H), 4.27 (t, J = 11.5 Hz, 1H), 2.03 (ddd, J = 13.8, 11.4, 4.7 Hz, 1H), 1.74 (td, J = 12.2, 11.2, 4.1 Hz, 2H), 1.46 (s, 3H), 1.43 - 1.20 (m, 4H), 0.99 - 0.85 (m, 3H).

Synthesis of (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol (1c). To compound 1b (14.01 g, 56.64 mmol) in THF (100 mL) at 0° C. was _{added a solution of LiBH 4} (57 mL, 114 mmol, 2.0 M in THF) and the reaction was allowed to warm to room temperature. After 2 h, the mixture was cooled to 0° C. and quenched with water (500 mL). The mixture was separated and the aqueous was extracted with EtOAc (300 mL×3). The combined organics were washed with water (500 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 1c. LC/MS (ESI) calculated for _{C 15} H ₂₆ NO ₂ : m/z 252.19, found 252.05 [M+H] ⁺ ; t _R =0.68 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.33 - 7.22 (m, 5H), 3.85 (dd, J = 9.4, 4.6 Hz, 1H), 3.60 (dd, J = 10.5, 4.6 Hz, 1H), 3.43 (dd, J = 10.5, 9.4 Hz, 1H), 3.37 (d, J = 11.2 Hz, 1H), 3.14 (d, J = 11.1 Hz, 1H), 2.31 (s, 3H), 1.37 - 1.23 (m, 1H), 1.23 - 1.00 (m, 4H), 0.96 (s, 1H), 0.78 (t, J = 6.9 Hz, 3H).

Synthesis of (R)-2-amino-2-methylhexan-1-ol (1d). To a mixture of compound 1c (14.24 g, 56.65 mmol) and 20% Pd(OH) _{2 on} carbon (2.85 g) in EtOH (210 mL) was added a solution of HCl (21.5 mL, 86.0 mmol, 4 M in dioxane) . The resulting mixture was purged with _{H 2} gas and then stirred at 70° C. under _{H 2 atmosphere.} After 10 h, the reaction mixture was cooled to room temperature, filtered through celite, rinsed with EtOH (50 mL) and concentrated in vacuo. The residue was co-evaporated with toluene (50 mL×1) to give compound 1d as HCl salt. LC/MS (ESI) calculated for _{C 7} H ₁₈ NO: m/z 132.13, found 131.90 [M+H] ⁺ ; t _R =0.42 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 3.54 (d, J = 11.4 Hz, 1H), 3.46 (d, J = 11.5 Hz, 1H), 1.65 (ddd, J = 14.0, 11.0, 5.8 Hz, 1H), 1.57 (dt, J = 13.8, 5.4 Hz, 1H), 1.44 - 1.26 (m, 4H), 1.24 (s, 3H), 0.95 (t, J = 7.0 Hz, 3H).

Synthesis of (R)-tert-butyl (1-hydroxy-2-methylhexan-2-yl)carbamate (1e). To a solution of 1d (1 g, 7.6 mmol) in THF (35 mL) was added saturated NaHCO _{3 (aq)} (35 mL) followed by di-tert-butyl dicarbonate (3.33 g, 15.24 mmol). After 24 hours, the organic solvent was removed under vacuum. The resulting slurry was diluted with water (50 mL), extracted with EtOAc (100 mL), washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 1e. LC/MS (ESI) calculated for _{C 12} H ₂₅ NO ₃ : m/z 232.18, found 231.61 [M+H] ⁺ ; t _R = 1.09 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 3.64 (d, J = 11.4 Hz, 1H), 3.59 (d, J = 11.5 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.56 - 1.45 (m , 1H), 1.43 (s, 9H), 1.37 - 1.27 (m, 4H), 1.16 (s, 3H), 0.91 (t, J = 7.0 Hz, 3H).

Synthesis of (R)-tert-butyl (2-methyl-1-oxohexan-2-yl)carbamate (1f). To a solution of 1e (2.1 g, 9.0 mmol) in DCM (100 mL) was added Dess-Martin periodinane (5.7 g, 14 mmol). After 2 h, the reaction was quenched with saturated Na ₂ S ₂ O _{3 (aq)} (75 mL). The mixture was separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give 1f. LC/MS (ESI) calculated for _{C 8} H ₁₅ NO ₃ : m/z 231.17, found 173.75 [M+H-(t-Bu)] ⁺ ; t _R = 1.18 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 9.36 (s, 1H), 1.98 - 1.78 (m, 1H), 1.70 - 1.61 (m, 1H), 1.44 (s, 9H), 1.35 (s, 3H) , 1.34 - 1.26 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H).

Synthesis of (R)-tert-butyl (1-(benzylamino)-2-methylhexan-2-yl)carbamate (1 g). To a solution of 1f (1.9 g, 8.4 mmol) in dry MeOH (50 mL) was added benzylamine (1.0 mL, 8.35 mmol). After 18 h, sodium borohydride (500 mg, 13 mmol) was added portionwise. After 60 min, the mixture was concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL), 1M NaOH _(aq.) (50 mL), 10% aqueous Rochelle salt solution (50 mL, supplied as a solid by Sigma-Aldrich), and brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 1 g. LC/MS (ESI) calculated for _{C 19} H ₃₂ N ₂ O ₂ m/z 321.25, found 321.03 [M+H] ⁺ ; t _R =0.94 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.35 - 7.31 (m, 5H), 3.86 - 3.78 (m, 2H), 2.82 - 2.69 (m, 1H), 2.66 - 2.54 (m, 1H), 1.42 ( s, 9H), 1.33 - 1.26 (m, 3H), 1.25 (s, 3H), 1.21 - 1.17 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

Synthesis of (R)-tert-butyl (1-(N-benzylacetamido)-2-methylhexan-2-yl)carbamate (1h). To a solution of 1 g (2.2 g, 6.9 mmol) in THF (50 mL) was added N,N-diisopropylethylamine (2.4 mL, 14 mmol) followed by acetyl chloride (0.75 mL, 11 mmol). After 60 min, the mixture was diluted with EtOAc (150 mL), washed with saturated NaHCO _{3 (aq)} (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. did it The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 1 h. LC/MS (ESI) calculated for _{C 21} H ₃₄ N ₂ O ₃ m/z 363.26, found 362.82 [M+H] ⁺ ; t _R =1.32 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.39 - 7.32 (m, 2H), 7.32 - 7.28 (m, 1H), 7.13 - 7.08 (m, 2H), 4.64 (dd, J = 17.4, 8.1 Hz, 2H), 2.12 (s, 3H), 1.78 - 1.65 (m, 2H), 1.41 (s, 9H), 1.34 - 1.22 (m, 7H), 0.89 (t, J = 7.0 Hz, 3H).

Synthesis of (R)-N-(2-amino-2-methylhexyl)acetamide (Ii). To a solution of 1 h (2.0 g, 5.4 mmol) in EtOH (55 mL) and HCl solution (2 mL, 4 M in dioxane) purged with Ar was added palladium hydroxide on carbon (2.0 g, 20 wt%). The mixture _{was purged with H 2} and heated to 70°C. After 24 h, the reaction mixture was filtered through celite, rinsed with EtOAc and concentrated in vacuo to give 1i as an HCl salt. LC/MS (ESI) calculated for _{C 9} H ₂₀ N ₂ O: m/z 173.16, found 172.92 [M+H] ⁺ ; t _R =0.50 min, on LC/MS method A.

¹ H NMR (400 MHz, MeOH- d ₄ ) δ 3.34 (d, J = 4.1 Hz, 2H), 2.02 (s, 3H), 1.66 - 1.57 (m, 2H), 1.45 - 1.33 (m, 4H), 1.29 (s, 3H), 0.98 (t, J = 6.9 Hz, 3H).

Synthesis of (R)-N-(2-((2-chloroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (1j). In a solution of 1i (202 mg, 0.97 mmol) and 2,4-dichloroquinazoline (500 mg, 0.97 mmol, supplied by AstaTech, Inc.) in THF (4 mL) N, N-diisopropylethylamine (0.67 mL, 3.87 mmol) was added. After stirring at 75° C. for 22 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give 1j as a mixture of isomers. LC/MS (ESI) calculated for _{C 17} H ₂₃ ClN ₄ O: m/z 335.15, found 335.20 [M+H] ⁺ ; t _R = 1.08 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 9.27 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.76 - 7.67 (m, 4H) ), 7.48 (ddt, J = 8.4, 5.3, 2.6 Hz, 3H), 6.59 (s, 1H), 5.65 (s, 1H), 3.83 (dd, J = 14.0, 5.0 Hz, 2H), 3.69 (dd, J = 14.1, 4.1 Hz, 1H), 3.20 (dd, J = 14.5, 6.1 Hz, 1H), 2.25 (t, J = 12.7 Hz, 1H), 2.13 (s, 2H), 2.09 (s, 3H), 2.02 - 1.88 (m, 2H), 1.77 - 1.64 (m, 2H), 1.57 (d, J = 4.6 Hz, 5H), 1.39 (s, 4H), 1.36 - 1.27 (m, 10H), 0.88 (td, J = 7.2, 6.8, 2.8 Hz, 9H).

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)-2-methylhexyl)acetamide (1k). To a solution of 1j (40.6 mg, 0.12 mmol) in 2-MeTHF (2 mL) by potassium carbonate (34.5 mg, 0.24 mmol) followed by 2,4-dimethoxybenzylamine (0.04 mL, 0.24 mmol, by Sigma-Aldrich supplied) was added. After stirring at 80° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 25% aq. acetonitrile - 70% aq. acetonitrile, gradient over 20 min) to give 1k as the TFA salt. . LC/MS (ESI) calculated for _{C 26} H ₃₅ N ₅ O ₃ m/z 466.27 found 466.39 [M+H] ⁺ ; t _R =0.99 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 9.51 (s, 1H), 8.72 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.53 (d) , J = 8.5 Hz, 1H), 7.30 (dd, J = 7.8, 2.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 2.6 Hz, 1H), 6.37 (d) , J = 8.4 Hz, 1H), 6.29 (s, 1H), 4.63 (d, J = 5.4 Hz, 2H), 3.91 - 3.83 (m, 1H), 3.82 (d, J = 2.2 Hz, 3H), 3.76 (d, J = 2.2 Hz, 3H), 3.01 (d, J = 14.6 Hz, 1H), 2.19 (d, J = 13.0 Hz, 1H), 2.11 (d, J = 2.8 Hz, 3H), 1.79 (t) , J = 13.1 Hz, 1H), 1.47 (d, J = 2.8 Hz, 3H), 1.21 - 1.06 (m, 4H), 0.83 (t, J = 6.7 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform- d ) δ -76.19.

Synthesis of (R)-N-(2-((2-aminoquinazolin-4-yl)amino)-2-methylhexyl)acetamide (1). To 1k (3.3 mg, 0.01 mmol) in DCM (1 mL) was added TFA (1.5 mL). After 4 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 1 as its TFA salt. LC/MS (ESI) calculated for _{C 17} H ₂₅ N ₅ O: m/z 316.21, found 316.22 [M+H] ⁺ ; t _R = 0.76 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.57 (t, J = 5.9 Hz, 1H), 8.18 - 8.01 (m, 1H), 7.78 (ddd, J = 8.4, 7.4, 1.2 Hz, 1H), 7.42 (ddd, J = 20.7, 9.8, 4.6 Hz, 2H), 3.89 (dd, J = 14.3, 5.8 Hz, 1H), 3.34 (d, J = 6.5 Hz, 1H), 2.23 - 2.10 (m, 2H) , 2.03 (s, 3H), 1.57 (s, 3H), 1.36 - 1.31 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.51.

Example 2

Synthesis of (R)-N-(2-((2-chloro-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (2a). In a solution of 1i (80.8 mg, 0.39 mmol) and 2,4-dichloro-7-fluoroquinazoline (84.8 mg, 0.39 mmol, supplied by Astattech, Inc.) in THF (1.6 mL) N,N -diisopropylethylamine (0.27 mL, 1.55 mmol) was added. After stirring at 75° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 2a. LC/MS (ESI) calculated for _{C 17} H ₂₂ ClFN ₄ O: m/z 353.15, found 353.17 [M+H] ⁺ ; t _R = 1.36 min, on LC/MS Method A.

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (2b) synthesis of. To a solution of 2a (64 mg, 0.18 mmol) in 2-MeTHF (2 mL) was added potassium carbonate (52.7 mg, 0.36 mmol) followed by 2,4-dimethoxybenzylamine (0.06 mL, 0.36 mmol). After stirring at 80° C. for 4 days, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 2b. LC/MS (ESI) calculated for _{C 26} H ₃₄ FN ₅ O ₃ : m/z 484.27, found 484.19 [M+H] ⁺ ; t _R = 1.29 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.59 (dd, J = 9.0, 5.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 9.7 Hz, 1H), 6.80 (td, J = 8.6, 2.6 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 8.3, 2.4 Hz, 1H), 4.63 - 4.51 (m, 2H), 3.86 - 3.79 (m, 4H), 3.78 (s, 3H), 3.21 (dd, J = 14.1, 6.4 Hz, 1H), 2.10 - 2.04 (m, 1H), 2.03 (s, 3H), 1.95 - 1.83 (m , 1H), 1.45 (s, 3H), 1.25 - 1.17 (m, 4H), 0.84 (t, J = 7.1 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform- d ) δ -108.10.

Synthesis of (R)-N-(2-((2-amino-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (2). To 2b (36.5 mg, 0.08 mmol) was added TFA (3 mL). After 90 min, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 2 as its TFA salt. LC/MS (ESI) calculated for _{C 17} H ₂₄ FN ₅ O: m/z 334.20, found 334.19 [M+H] ⁺ ; t _R =0.99 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.77 (s, 1H), 8.18 (dd, J = 9.1, 5.4 Hz, 1H), 7.22 - 7.11 (m, 2H), 3.86 (d, J = 14.2) Hz, 1H), 3.33 (d, J = 14.1 Hz, 1H), 2.12 (t, J = 7.9 Hz, 2H), 2.02 (s, 3H), 1.55 (s, 3H), 1.37 - 1.26 (m, 4H) ), 0.90 (t, J = 7.0 Hz, 3H).

Example 3

Synthesis of (R)-N-(2-((2-chloro-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (3a). of 1i (80.8 mg, 0.39 mmol) and 2,4-dichloro-6,7-difluoroquinazoline (90.1 mg, 0.39 mmol, supplied by Matrix Scientific) in THF (1.6 mL) To the solution was added N,N-diisopropylethylamine (0.27 mL, 0.15 mmol). After stirring at 75° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 3a. LC/MS (ESI) calculated for _{C 17} H ₂₁ ClF ₂ N ₄ O: m/z 371.14, found 371.12 [M+H] ⁺ ; t _R = 1.51 min, on LC/MS method A.

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide Synthesis of (3b). To a solution of 3a (78.9 mg, 0.21 mmol) in 2-MeTHF (2 mL) was added potassium carbonate (61.5 mg, 0.43 mmol) followed by 2,4-dimethoxybenzylamine (0.06 mL, 0.43 mmol). After stirring at 80° C. for 4 days, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give 3b. LC/MS (ESI) calcd for _{C 26} H ₃₃ F ₂ N ₅ O ₃ m/z 502.26, found 502.25 [M+H] ⁺ ; t _R =1.32 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.44 (dd, J = 10.9, 8.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.10 (dd, J = 11.5, 7.8 Hz, 1H) ), 6.75 (s, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.40 (dd, J = 8.3, 2.4 Hz, 1H), 6.09 (s, 1H), 5.29 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.85 - 3.78 (m, 4H), 3.78 (s, 3H), 3.17 (dd, J = 14.2, 6.4 Hz, 1H), 2.12 - 2.06 (m, 1H), 2.05 (s, 3H), 1.94 - 1.83 (m, 1H), 1.46 (s, 3H), 1.27 - 1.19 (m, 4H), 0.85 (t, J = 6.4 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform- d ) δ -131.08, -144.04.

Synthesis of (R)-N-(2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (3). To 3b (32.9 mg, 0.07 mmol) was added TFA (3 mL). After 1 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 3 as its TFA salt. LC/MS (ESI) calculated for _{C 17} H ₂₃ F ₂ N ₅ O: m/z 352.19, found 352.17 [M+H] ⁺ ; t _R =1.03 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.70 (s, 1H), 8.17 (dd, J = 11.0, 7.8 Hz, 1H), 7.36 (dd, J = 10.6, 6.9 Hz, 1H), 3.87 ( d, J = 14.2 Hz, 1H), 3.38 (d, J = 14.2 Hz, 1H), 2.17 (ddd, J = 13.8, 9.7, 6.3 Hz, 1H), 2.06 (dd, J = 10.7, 5.3 Hz, 1H) ), 2.02 (s, 3H), 1.54 (s, 3H), 1.35 - 1.27 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.84, -127.42 - -129.14 (m), -141.96 (ddd, J = 21.6, 10.9, 6.8 Hz).

Example 4

Synthesis of (R)-N-(2-((2-chloropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (4a). A solution of 1i (80.8 mg, 0.39 mmol) and 2,4-dichloropyrido[3,4-d]pyrimidine (78.1 mg, 0.39 mmol, supplied by Astatech, Inc.) in THF (1.6 mL) to N,N-diisopropylethylamine (0.27 mL, 1.5 mmol) was added. After stirring at 75° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 4a. LC/MS (ESI) calculated for _{C 16} H ₂₂ ClN ₅ O: m/z 336.15, found 336.12 [M+H] ⁺ ; t _R =1.14 min, on LC/MS method A.

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acet Synthesis of amide (4b). To a solution of 4a (43.7 mg, 0.13 mmol) in 2-MeTHF (2 mL) was added potassium carbonate (36.3 mg, 0.26 mmol) followed by 2,4-dimethoxybenzylamine (0.04 mL, 0.26 mmol). After stirring at 80° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give 4b. LC/MS (ESI) calculated for _{C 25} H ₃₄ N ₆ O ₃ : m/z 467.27, found 467.21 [M+H] ⁺ ; t _R =1.11 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 8.80 (s, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.22 (s, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.40 (d, J = 8.5 Hz, 1H), 6.16 (s, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.83 (s, 5H), 3.78 (s, 3H), 3.14 (dd, J = 14.5, 6.3 Hz, 1H), 2.13 (t, J = 14.2 Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 1.93 - 1.82 (m, 2H), 1.48 (s, 3H), 1.23 (m, 4H), 0.85 (t, J = 6.7 Hz, 3H).

Synthesis of (R)-N-(2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (4). To 4b (16.8 mg, 0.04 mmol) was added TFA (3 mL). After 24 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 4 as its TFA salt. LC/MS (ESI) calculated for _{C 16} H ₂₄ N ₆ O: m/z 317.20, found 317.17 [M+H] ⁺ ; t _R = 0.85 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.17 (s, 1H), 8.79 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 5.5 Hz, 1H) , 3.87 (d, J = 14.3 Hz, 1H), 3.36 (d, J = 14.3 Hz, 1H), 2.23 - 2.07 (m, 2H), 2.02 (s, 3H), 1.57 (s, 3H), 1.38 - 1.31 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.93.

Example 5

Synthesis of (R)-N-(2-((2-chloropyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (5a). 1i (106 mg, 0.50 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (100 mg, 0.50 mmol, supplied by Combi-Blocks) in THF (2 mL) ) was added N,N-diisopropylethylamine (0.35 mL, 2.0 mmol). After stirring at 80° C. for 2 h, the reaction was cooled to room temperature, diluted with EtOAc (15 mL), washed with water (15 mL) and brine (15 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 5a. LC/MS (ESI) calcd for _{C 16} H ₂₂ ClN ₅ O: m/z 336.15, found 336.21 [M+H] ⁺ ; t _R =0.94 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 8.96 (dd, J = 4.4, 1.8 Hz, 1H), 8.49 (s, 1H), 8.38 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (dd , J = 8.2, 4.5 Hz, 1H), 6.72 (t, J = 6.9 Hz, 1H), 3.85 (dd, J = 14.5, 6.7 Hz, 1H), 3.14 (dd, J = 14.5, 6.3 Hz, 1H) , 2.36 (td, J = 13.4, 12.7, 4.4 Hz, 1H), 2.16 (s, 3H), 1.92 (td, J = 13.8, 12.8, 3.9 Hz, 1H), 1.59 (s, 3H), 1.41 - 1.22 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H).

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acet Synthesis of amide (5b). To a solution of 5a (128.5 mg, 0.38 mmol) in 2-MeTHF (2.5 mL) was added potassium carbonate (107 mg, 0.77 mmol) followed by 2,4-dimethoxybenzylamine (0.12 mL, 0.77 mmol). After stirring at 80° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (15 mL), washed with water (15 mL) and brine (15 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 5b. LC/MS (ESI) calculated for _{C 25} H ₃₄ N ₆ O ₃ : m/z 467.27, found 467.40 [M+H] ⁺ ; t _R =0.90 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 8.36 (s, 1H), 8.17 (s, 1H), 7.17 (s, 1H), 7.00 (dd, J = 8.1, 4.6 Hz, 1H), 6.46 (d) , J = 2.4 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 4.76 - 4.48 (m, 2H), 3.85 - 3.80 (m, 1H), 3.79 (s, 6H), 3.15 (dd, J = 14.3, 6.1 Hz, 1H), 2.18 (s, 1H), 2.11 (s, 3H), 1.84 (s, 1H), 1.51 (s, 3H), 1.17 (s, 4H), 0.83 (s, 3H) ).

Synthesis of (R)-N-(2-((2-aminopyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (5). To 5b (168.5 mg, 0.36 mmol) was added TFA (3 mL). After 24 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 5 as its TFA salt. LC/MS (ESI) calculated for _{C 16} H ₂₄ N ₆ O: m/z 317.20, found 317.24 [M+H] ⁺ ; t _R =0.64 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.05 (s, 1H), 8.73 (dd, J = 4.7, 1.6 Hz, 1H), 8.55 (dd, J = 8.2, 1.6 Hz, 1H), 7.46 ( dd, J = 8.2, 4.7 Hz, 1H), 3.87 (dd, J = 14.3, 5.3 Hz, 1H), 3.40 - 3.33 (m, 1H), 2.23 - 2.04 (m, 2H), 2.02 (s, 3H) , 1.57 (s, 3H), 1.39 - 1.28 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.93.

Example 6

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-2-methylhexyl ) Synthesis of acetamide (6a).

A solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (supplied by Astatech, Inc.) (100 mg, 0.49 mmol) in THF (10 mL) was prepared with 1i (200 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 mmol). After the mixture was stirred at reflux for 12 h, 2,4-dimethoxybenzylamine (0.38 mL, 2.5 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and the mixture was micro The wave reactor was heated to 115° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (100 mL), washed with water (100 mL), brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was subjected to silica gel flash chromatography eluting with 0-100% EtOAc in hexanes to give 6a.

LCMS ( m/z ): 470.21 [M+H] ⁺ .

Synthesis of (R)-N-(2-((2-amino-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (6). 6a (60 mg, 0.133 mmol) was dissolved in TFA (3 mL). After 60 min, the mixture was concentrated in vacuo. The residue was taken up in MeOH, filtered and concentrated in vacuo to give the title compound 6 as its TFA salt.

¹ H NMR (400 MHz, MeOH- d ₄ ) 8.65 (dd, J = 4.3, 1.5 Hz, 1H), 7.86 - 7.73 (m, 2H), 4.68 - 4.55 (m, 4H), 3.59 (dd, J = 13.9, 4.3 Hz, 4H), 3.34 - 3.23 (m, 3H), 1.88 (s, 3H), 1.78 - 1.67 (m, 2H), 1.39 (ddd, J = 7.7, 5.1, 2.4 Hz, 4H), 0.91 (ddt, J = 8.3, 4.7, 3.0 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-d ₄ ) δ -77.7.

LC/MS 320.15 [M+H] ⁺ ; t _R = 0.91 min (LC/MS HPLC Method A).

Example 7

Synthesis of 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (7a). tert-Butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (500 mg, 1.64 mmol, Astatech) in DCM (10 mL) , Inc.) was added a solution of HCl (1 mL, 4.0 mmol, 4 M in dioxane). After 3 days, the reaction was concentrated in vacuo to give 7a as HCl salt. LC/MS (ESI) calculated for _{C 7} H ₇ Cl ₂ N ₃ : m/z 204.00, found 204.00 [M+H] ⁺ ; t _R = 0.25 min, on LC/MS method A.

Synthesis of 1-(2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one (7b). To 7a (401.9 mg, 1.64 mmol) in THF (20 mL) was added triethylamine (0.55 mL, 3.95 mmol) followed by acetyl chloride (0.15 mL, 2.11 mmol). After 60 min, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with saturated NaHCO _{3 (aq)} (30 mL) and brine (30 mL). The combined aqueous portions were extracted with EtOAc (50 mL). The combined organics were _{dried over Na 2} SO ₄ and concentrated in vacuo to give 7b. LC/MS (ESI) calculated for _{C 9} H ₉ Cl ₂ N ₃ O: m/z 246.01, found 246.14 [M+H] ⁺ ; t _R =0.68 min, on LC/MS method A.

(R)-N-(2-((6-acetyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-2- Synthesis of methylhexyl)acetamide (7c). To a solution of 7b (420.7 mg, 1.64 mmol) and 1i (363.9 mg, 1.64 mmol) in NMP (6.5 mL) was added N,N-diisopropylethylamine (0.60 mL, 3.29 mmol). After stirring at 150° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed with water (30 mL). The aqueous was extracted with EtOAc (30 mL). The combined organics were washed with brine (3×50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with EtOAc-MeOH to give 7c as a mixture of products. LC/MS (ESI) calculated for _{C 18} H ₂₈ ClN ₅ O ₂ : m/z 382.19, found 382.29 [M+H] ⁺ ; t _R = 0.88 min, on LC/MS method A.

(R)-N-(2-((6-acetyl-2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyri Synthesis of midin-4-yl)amino)-2-methylhexyl)acetamide (7d). To a solution of 7c (418.1 mg, 1.10 mmol) in 2-MeTHF (10 mL) in a sealed container was added potassium carbonate (303.9 mg, 2.19 mmol) followed by 2,4-dimethoxybenzylamine (0.82 mL, 5.47 mmol) added. After stirring at 150° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with water (15 mL) and brine (15 mL). The combined aqueous portions were extracted with EtOAc (50 mL). The combined organics were _{dried over Na 2} SO ₄ , then filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 25% aq. acetonitrile - 45% aq. acetonitrile, gradient over 12 min) to give 7d as the TFA salt. LC/MS (ESI) calculated for _{C 27} H ₄₀ N ₆ O ₄ : m/z 513.31, found 513.46 [M+H] ⁺ ; t _R = 0.88 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 9.12 (dt, J = 70.2, 5.8 Hz, 1H), 7.54 (d, J = 168.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.46 - 6.40 (m, 1H), 6.37 (dt, J = 8.3, 2.1 Hz, 1H), 6.16 (dt, J = 72.4, 6.6 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.41 - 4.22 (m, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.69 (dt, J = 21.6, 6.8 Hz, 3H), 2.97 (ddd, J = 38.6, 14.6, 6.3 Hz, 1H) ), 2.82 (t, J = 5.1 Hz, 1H), 2.73 (t, J = 6.0 Hz, 1H), 2.21 (d, J = 34.6 Hz, 3H), 2.07 (d, J = 2.4 Hz, 3H), 2.05 - 1.97 (m, 1H), 1.81 - 1.67 (m, 1H), 1.39 (d, J = 11.7 Hz, 3H), 1.21 - 0.98 (m, 4H), 0.85 (t, J = 6.6 Hz, 3H) . ¹⁹ F NMR (377 MHz, chloroform- d ) δ -76.33.

(R)-N-(2-((6-acetyl-2-amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-2- Synthesis of methylhexyl)acetamide (7). To 7d (53.6 mg, 0.11 mmol) was added TFA (3 mL). After 3 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 7 as its TFA salt. LC/MS (ESI) calculated for _{C 18} H ₃₀ N ₆ O ₂ m/z 363.24, found 363.36 [M+H] ⁺ ; t _R =0.65 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 (d, J = 154.6 Hz, 1H), 4.41 - 4.20 (m, 2H), 4.02 - 3.60 (m, 5H), 3.20 (dd, J = 31.3) , 14.2 Hz, 1H), 2.70 (dt, J = 47.8, 5.9 Hz, 2H), 2.22 (d, J = 18.5 Hz, 3H), 2.17 - 2.07 (m, 1H), 2.02 (d, J = 5.5 Hz) , 3H), 2.00 - 1.92 (m, 1H), 1.49 (d, J = 15.4 Hz, 3H), 1.38 - 1.15 (m, 4H), 0.91 (td, J = 7.1, 3.3 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.86.

Example 8

Synthesis of 2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (8a). tert-Butyl 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (500 mg, 1.64 mmol, Astatech) in DCM (10 mL) , Inc.) was added a solution of HCl (2 mL, 8.0 mmol, 4 M in dioxane). After 18 h, the reaction was concentrated in vacuo to give 8a as an HCl salt. LC/MS (ESI) calculated for _{C 7} H ₇ Cl ₂ N ₃ : m/z 204.00, found 204.00 [M+H] ⁺ ; t _R =0.38 min, on LC/MS method A.

Synthesis of 1-(2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)ethan-1-one (8b). To 8a (20 mL) in THF was added triethylamine (0.55 mL, 3.95 mmol) followed by acetyl chloride (0.14 mL, 1.97 mmol). After 60 min, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with saturated NaHCO _{3 (aq)} (30 mL) and brine (30 mL). The combined aqueous portions were extracted with EtOAc (50 mL). The combined organics were _{dried over Na 2} SO ₄ and concentrated in vacuo to give 8b. LC/MS (ESI) calculated for _{C 9} H ₉ Cl ₂ N ₃ O: m/z 246.01, found 246.76 [M+H] ⁺ ; t _R = 0.74 min, on LC/MS method A.

(R)-N-(2-((7-acetyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2- Synthesis of methylhexyl)acetamide (8c). To a solution of 8b (550.1 mg, 1.64 mmol) and 1i (360.4 mg, 1.64 mmol) in NMP (6.5 mL) was added N,N-diisopropylethylamine (0.60 mL, 3.29 mmol). After stirring at 150° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed with water (30 mL). The aqueous was extracted with EtOAc (30 mL). The combined organics were washed with brine (3×50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with EtOAc-MeOH to give 8c as a mixture of products. LC/MS (ESI) calculated for _{C 18} H ₂₈ ClN ₅ O ₂ : m/z 382.19, found 382.29 [M+H] ⁺ ; t _R = 0.88 min, on LC/MS method A.

(R)-N-(2-((7-acetyl-2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyri) Synthesis of midin-4-yl)amino)-2-methylhexyl)acetamide (8d). To a solution of 8c (173.9 mg, 0.46 mmol) in 2-MeTHF (4.5 mL) in a sealed vessel was added potassium carbonate (131.7 mg, 0.91 mmol) followed by 2,4-dimethoxybenzylamine (0.35 mL, 2.28 mmol) added. After stirring at 150° C. for 18 h, the reaction was cooled to room temperature, diluted with EtOAc (30 mL), washed with water (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 25% aq. acetonitrile - 45% aq. acetonitrile, gradient over 15 min) to give 8d as the TFA salt. LC/MS (ESI) calculated for _{C 27} H ₄₀ N ₆ O ₄ : m/z 513.31, found 513.41 [M+H] ⁺ ; t _R = 0.89 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.93 - 7.68 (m, 1H), 7.36 (d, J = 39.2 Hz, 1H), 7.05 (dd, J = 8.3, 4.7 Hz, 1H), 6.45 (dd , J = 4.4, 2.3 Hz, 1H), 6.38 (dd, J = 8.2, 2.7 Hz, 1H), 4.51 (dd, J = 12.8, 7.0 Hz, 4H), 3.80 (d, J = 6.1 Hz, 3H) , 3.78 (d, J = 3.4 Hz, 3H), 3.76 - 3.66 (m, 2H), 3.07 (dd, J = 14.6, 6.2 Hz, 1H), 2.47 - 2.29 (m, 2H), 2.21 (s, 3H) ), 2.13 (d, J = 16.1 Hz, 3H), 2.09 - 2.01 (m, 1H), 1.85 - 1.72 (m, 1H), 1.45 (d, J = 2.3 Hz, 3H), 1.32 - 1.16 (m, 4H), 0.87 (td, J = 7.0, 3.7 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform- d ) δ -76.44.

(R)-N-(2-((7-acetyl-2-amino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2- Synthesis of methylhexyl)acetamide (8). To 8d (65.5 mg, 0.13 mmol) was added TFA (3 mL). After 3 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 7 as its TFA salt. LC/MS (ESI) calculated for _{C 18} H ₃₀ N ₆ O ₂ m/z 363.33, found 363.36 [M+H] ⁺ ; t _R =0.65 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.55 (d, J = 23.4 Hz, 1H), 4.50 (d, J = 1.8 Hz, 2H), 3.93 - 3.70 (m, 5H), 3.18 (dd, J = 14.2, 4.7 Hz, 1H), 2.41 (dt, J = 38.3, 6.0 Hz, 2H), 2.19 (d, J = 12.0 Hz, 3H), 2.13 - 2.05 (m, 1H), 2.01 (d, J) = 5.8 Hz, 3H), 2.00 - 1.90 (m, 1H), 1.48 (d, J = 3.0 Hz, 3H), 1.41 - 1.15 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.91.

Example 9

Synthesis of (R)-N-(2-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (9a). 1i (204 mg, 0.98 mmol) and 2,4-dichlorothieno[3,2-d]pyrimidine (200 mg, 0.975 mmol, Synthonix) in 2,4-dioxane (4 mL) to a solution of Na ₂ CO ₃ (420 mg, 3.90 mmol) was added. After stirring at 85° C. for 3 days, the reaction was cooled to room temperature, diluted with EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na ₂ SO ₄ , Filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 9a. LC/MS (ESI) calculated for _{C 15} H ₂₁ ClN ₄ OS: m/z 341.11, found 341.12 [M+H] ⁺ ; t _R = 1.26 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.71 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 5.3 Hz, 1H), 5.72 (s, 1H), 3.84 (dd, J = 13.9) , 5.4 Hz, 1H), 3.70 (dd, J = 13.9, 4.8 Hz, 1H), 1.88 (td, J = 13.1, 11.6, 3.2 Hz, 1H), 1.66 (td, J = 14.2, 12.3, 4.4 Hz, 1H), 1.35 (s, 3H), 1.31 (tt, J = 6.2, 3.3 Hz, 4H), 0.90 (t, J = 6.7 Hz, 3H).

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (9b) synthesis of. To a solution of 9a (188.7 mg, 0.55 mmol) in 2-MeTHF (4 mL) was added potassium carbonate (158 mg, 0.11 mmol) followed by 2,4-dimethoxybenzylamine (0.17 mL, 1.11 mmol). After stirring at 85° C. for 18 h, the reaction was cooled to room temperature, washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to give 9b. LC/MS (ESI) calculated for _{C 24} H ₃₃ N ₅ O ₃ S: m/z 472.23, found 472.23 [M+H] ⁺ ; t _R = 1.23 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.55 (d, J = 5.3 Hz, 1H), 7.24 (s, 1H), 7.12 (d, J = 5.3 Hz, 1H), 6.45 (d, J = 2.4) Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 4.57 (dd, J = 5.9, 1.5 Hz, 4H), 3.88 (dd, J = 14.0, 6.0 Hz, 1H), 3.82 (s) , 3H), 3.78 (s, 3H), 3.56 (dd, J = 14.1, 5.8 Hz, 1H), 1.92 (s, 3H), 1.78 (dq, J = 15.1, 8.6, 7.8 Hz, 1H), 1.35 ( s, 4H), 1.34 - 1.25 (m, 7H), 0.94 - 0.86 (m, 3H).

Synthesis of (R)-N-(2-((2-aminothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (9). To 9b (12.9 mg, 0.03 mmol) was added TFA (3 mL). After 2 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 9 as its TFA salt. LC/MS (ESI) calculated for _{C 15} H ₂₃ N ₅ OS: m/z 322.16, found 322.16 [M+H] ⁺ ; t _R =0.92 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.09 (d, J = 5.4 Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 4.08 (d, J = 13.7 Hz, 1H), 3.77 (d, J = 13.7 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.91 (s, 3H), 1.58 - 1.47 (m, 1H), 1.35 - 1.29 (m, 4H), 1.28 (s, 3H) ), 0.92 (t, J = 6.8 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.85.

Example 10

Synthesis of tert-butyl (R)-(1-hydroxyhexan-2-yl)carbamate (18a). To a solution of (R)-norleucinol (4.0 g, 34.1 mmol, supplied by Astatech Inc.) in DCM (150 mL) was di-tert-butyl dicarbonate (14.9 g, 68.3 mmol) followed by N ,N-diisopropylethylamine (6.0 mL, 34.1 mmol) was added. After stirring at 40° C. for 18 h, the reaction was cooled to ambient temperature, washed with water (75 mL) and brine (75 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to silica gel chromatography with ELSD eluting with hexanes-EtOAc to give 10a. LC/MS (ESI) calculated for _{C 11} H ₂₃ NO ₃ : m/z 218.17, found 217.70 [M+H] ⁺ ; t _R = 0.93 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 4.59 (s, 1H), 3.67 (dd, J = 10.5, 3.4 Hz, 1H), 3.61 (s, 1H), 3.53 (dd, J = 10.5, 5.7 Hz) , 1H), 2.18 (s, 1H), 1.57 - 1.47 (m, 1H), 1.45 (s, 9H), 1.43 - 1.38 (m, 1H), 1.39 - 1.29 (m, 4H), 0.97 - 0.83 (m) , 3H).

Synthesis of tert-butyl (R)-(1-(1,3-dioxoisoindolin-2-yl)hexan-2-yl)carbamate (10b). To a solution of 10a (7.10 g, 32.1 mmol) in THF (33 mL) followed by triphenylphosphine (10.5 g, 42.5 mmol) followed by phthalimide (6.3 g, 42.5 mmol) and diisopropyl azodicarboxylate ( 8.4 mL, 42.5 mmol) was added. After stirring at ambient temperature for 18 h, the reaction is diluted with EtOAc (75 mL), washed with water (75 mL) and brine (100 mL), dried over Na ₂ SO ₄ , then filtered and under vacuum. concentrated. The residue was then triturated with ether, filtered and concentrated several times in vacuo. The residue was subjected to silica gel chromatography eluting with hexane-EtOAc to give 10b. LC/MS (ESI) calculated for _{C 19} H ₂₆ N ₂ O ₄ : m/z 347.19, found 346.37 [M+H] ⁺ ; t _R =1.01 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (dd, J = 5.3, 3.0 Hz, 2H), 4.52 (d, J = 9.5 Hz, 1H) ), 3.97 (s, 1H), 3.79 - 3.53 (m, 2H), 1.64 - 1.27 (m, 6H), 1.22 (s, 9H), 0.91 (t, J = 7.1 Hz, 3H).

Synthesis of tert-butyl (R)-(1-aminohexan-2-yl)carbamate (10c). To a solution of 10b (1.21 g, 3.49 mmol) in EtOH (35 mL) was added hydrazine monohydrate (0.34 mL, 6.98 mmol). After stirring at 80° C. for 18 h, the reaction was cooled to ambient temperature, diluted with ether (50 mL), filtered, rinsed with ether (30 mL) and concentrated in vacuo to afford 10c.

¹ H NMR (400 MHz, chloroform- d ) δ 3.52 (s, 1H), 2.78 (dd, J = 13.1, 4.5 Hz, 1H), 2.63 (dd, J = 13.1, 6.8 Hz, 1H), 1.44 (s) , 9H), 1.40 - 1.27 (m, J = 3.7 Hz, 6H), 0.89 (t, J = 6.3 Hz, 3H).

Synthesis of tert-butyl (R)-(1-acetamidohexan-2-yl)carbamate (10d). To a solution of 10c (0.68 g, 3.15 mmol) in THF (100 mL) was added N,N-diisopropylethylamine (0.88 mL, 6.31 mmol) followed by acetyl chloride (0.337 mL, 4.72 mmol). After stirring at ambient temperature for 1 h, the reaction is diluted with EtOAc (120 mL), washed with saturated sodium bicarbonate solution (150 mL) and brine (75 mL), dried over Na ₂ SO ₄ then filtered and , and concentrated in vacuo to give crude 10d. LC/MS (ESI) calculated for _{C 13} H ₂₆ N ₂ O ₃ : m/z 259.19, found 258.81 [M+H] ⁺ ; t _R =0.90 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 3.72 - 3.50 (m, 1H), 3.30 - 3.09 (m, 2H), 1.90 (s, 3H), 1.38 (s, 9H), 1.34 - 1.09 (m, 6H), 0.83 (t, J = 6.8, 6.1 Hz, 3H).

Synthesis of (R)-N-(2-aminohexyl)acetamide (10e). To a solution of 10d (813 mg, 3.15 mmol) in DCM (6 mL) was added HCl solution (3.2 mL, 4 M in dioxane). After stirring at ambient temperature for 18 h, the solution was concentrated in vacuo to give crude 10e as HCl salt. LC/MS (ESI) calculated for _{C 8} H ₁₈ N ₂ O: m/z 159.14, found 159.98 [M+H] ⁺ ; t _R =0.49 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 3.14 - 3.04 (m, 1H), 2.10 (s, 3H), 1.80 - 1.61 (m, 2H), 1.29 - 1.23 (m, 4H), 0.96 - 0.82 ( m, 3H).

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)hexyl)acetamide (10 g). To a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) and 10e (107.6 mg, 0.502 mmol) in THF (2 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) did. After stirring at 75° C. for 18 h, 2,4-dimethoxybenzylamine (0.17 mL, 1.1 mmol) was added followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol). The reaction is heated in a microwave reactor at 125° C. for 30 min, the solution is diluted with EtOAc (60 mL), washed with water (50 mL) and brine (60 mL), dried over Na ₂ SO ₄ , and filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting in hexanes-EtOAc followed by EtOAc-MeOH to give 10 g as a mixture of isomers. LC/MS (ESI) calculated for _{C 25} H ₃₃ N ₅ O ₃ : m/z 452.26, found 452.37 [M+H] ⁺ ; t _R =1.01 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.62 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.21 ( t, J = 9.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 8.1, 2.3 Hz, 1H), 4.59 ( d, J = 5.8 Hz, 2H), 4.41 - 4.13 (m, 1H), 3.84 (d, J = 2.8 Hz, 3H), 3.77 (d, J = 1.5 Hz, 3H), 3.66 - 3.51 (m, 1H) ), 3.37 (dt, J = 15.0, 4.2 Hz, 1H), 1.94 (dd, J = 29.2, 2.2 Hz, 3H), 1.75 - 1.64 (m, 1H), 1.63 - 1.52 (m, 1H), 1.47 - 1.34 (m, 2H), 1.33 - 1.28 (m, 2H), 0.90 (dt, J = 29.0, 7.1 Hz, 3H).

Synthesis of (R)-N-(2-((2-aminoquinazolin-4-yl)amino)hexyl)acetamide (10). To 10 g (67.3 mg, 0.15 mmol) was added TFA (3 mL). After 90 min, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 20% aq. acetonitrile - 40% aq. acetonitrile, gradient over 10 min) to give 10 as its TFA salt. LC/MS (ESI) calculated for _{C 16} H ₂₃ N ₅ O: m/z 302.19, found 302.24 [M+H] ⁺ ; t _R =0.64 min, on LC/MS Method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.03 (dt, J = 8.4, 1.0 Hz, 1H), 7.77 (ddt, J = 8.4, 7.2, 1.1 Hz, 1H), 7.42 (tdd, J = 7.2) , 2.4, 1.2 Hz, 2H), 4.23 (tt, J = 9.1, 4.6 Hz, 1H), 3.82 (dd, J = 13.4, 4.6 Hz, 1H), 3.58 (dd, J = 13.6, 8.4 Hz, 1H) , 1.92 (s, 3H), 1.63 (ddt, J = 14.0, 9.3, 4.8 Hz, 1H), 1.51 (dtd, J = 13.8, 9.3, 4.1 Hz, 1H), 1.46 - 1.28 (m, 4H), 0.93 (t, J = 6.6 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.86.

Example 11

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoroquinazolin-4-yl)amino)hexyl)acetamide (11b). To a solution of 2,4-dichloro-7-fluoroquinazoline (100 mg, 0.46 mmol) and 10e (90 mg, 0.46 mmol) in THF (2 mL) N,N-diisopropylethylamine (0.32 mL, 1.8 mmol) was added. After stirring at 75° C. for 18 h, 2,4-dimethoxybenzylamine (0.21 mL, 1.4 mmol) was added followed by N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The reaction was heated in a microwave reactor at 125° C. for 30 min, diluted with EtOAc (70 mL), washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , filtered, and Concentrated in vacuo. The residue was chromatographed on silica gel eluting in hexanes-EtOAc followed by EtOAc-MeOH to give 11b. LC/MS (ESI) calculated for _{C 25} H ₃₂ FN ₅ O ₃ : m/z 470.25, found 470.34 [M+H] ⁺ ; t _R =0.99 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.55 (dd, J = 9.0, 6.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 11.1 Hz, 1H), 6.79 (t, J = 8.9 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.40 (dd, J = 8.2, 1.9 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.75 - 3.68 (m, 1H), 3.62 (d, J = 11.3 Hz, 1H), 3.35 (d, J = 14.1 Hz, 1H), 1.85 (s) , 3H), 1.74 - 1.64 (m, 1H), 1.64 - 1.52 (m, 1H), 1.40 - 1.29 (m, 4H), 0.94 - 0.84 (m, 3H).

Synthesis of (R)-N-(2-((2-amino-7-fluoroquinazolin-4-yl)amino)hexyl)acetamide (11). To 11b (73.7 mg, 0.16 mmol) was added TFA (3 mL). After 90 min, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 20% aq. acetonitrile - 40% aq. acetonitrile, gradient over 10 min) to give 11 as its TFA salt. LC/MS (ESI) calculated for _{C 16} H ₂₂ FN ₅ O: m/z 320.18, found 320.28 [M+H] ⁺ ; t _R =0.70 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.10 (dd, J = 9.0, 5.4 Hz, 1H), 7.18 (ddd, J = 18.6, 9.1, 2.5 Hz, 2H), 4.22 (dq, J = 12.9) , 4.5 Hz, 1H), 3.81 (dd, J = 13.4, 4.6 Hz, 1H), 3.56 (dd, J = 13.4, 8.3 Hz, 1H), 1.92 (s, 3H), 1.69 - 1.56 (m, 1H) , 1.56 - 1.45 (m, 1H), 1.45 - 1.29 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.85, -103.53 -104.38 (m).

Example 12

Synthesis of (R)-N-(2-((2-chloro-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide (12a). To a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.00 g, 0.43 mmol) and 10e (91 mg, 0.47 mmol) in THF (2.4 mL) N,N-diisopropylethylamine ( 0.15 mL, 0.85 mmol) was added. After stirring at ambient temperature for 18 h, the solution is diluted with EtOAc (75 mL), washed with water (50 mL) and brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. and crude 12a was obtained. LC/MS (ESI) calculated for _{C 16} H ₁₉ ClF ₂ N ₄ O: m/z 357.12, found 357.23 [M+H] ⁺ ; t _R = 1.09 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.46 (dd, J = 10.7, 7.6 Hz, 1H), 7.31 (dd, J = 15.2, 8.7 Hz, 1H), 4.47 - 4.30 (m, 1H), 3.66 (dt, J = 9.2, 2.9 Hz, 1H), 3.39 (ddd, J = 14.4, 5.1, 3.1 Hz, 1H), 1.99 (s, 3H), 1.74 (t, J = 9.0 Hz, 1H), 1.59 ( t, J = 6.2 Hz, 1H), 1.40 - 1.31 (m, 4H), 0.86 - 0.77 (m, 3H).

of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide (12b) synthesis. To a solution of 12a (152 mg, 0.43 mmol) in THF (3 mL) 2,4-dimethoxybenzylamine (0.19 mL, 1.28 mmol) followed by N,N-diisopropylethylamine (0.22 mL, 1.28 mmol) was added. The reaction was heated in a microwave reactor at 140° C. for 1 h, the solution was diluted with hexane-EtOAc (1:3, 75 mL), washed with water (2×50 mL) and brine (75 mL), Na _{dried over 2} SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting in hexanes-EtOAc followed by EtOAc-MeOH to give 12b. LC/MS (ESI) calculated for _{C 25} H ₃₁ F ₂ N ₅ O ₃ : m/z 488.24, found 488.33 [M+H] ⁺ ; t _R = 1.16 min, on LC/MS method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.45 (dt, J = 10.8, 7.7 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.18 - 7.07 (m, 1H), 6.45 (d) , J = 2.3 Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 4.56 (dd, J = 5.9, 3.0 Hz, 2H), 4.41 - 4.30 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.56 - 3.45 (m, 1H), 3.33 (dt, J = 14.0, 4.1 Hz, 1H), 1.83 (s, 3H), 1.76 - 1.61 (m, 1H), 1.60 - 1.49 (m, 1H), 1.36 - 1.28 (m, 4H), 0.87 (t, J = 6.8 Hz, 3H).

Synthesis of (R)-N-(2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide (12). To 12b (26.0 mg, 0.05 mmol) was added TFA (3 mL). After 90 min, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 12 as its TFA salt. LC/MS (ESI) calculated for _{C 16} H ₂₁ F ₂ N ₅ O: m/z 338.17, found 338.30 [M+H] ⁺ ; t _R = 0.74 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.21 (dd, J = 10.9, 7.9 Hz, 1H), 7.37 (dd, J = 10.6, 6.8 Hz, 1H), 4.66 (qd, J = 7.4, 4.1) Hz, 1H), 3.57 (dd, J = 13.9, 4.2 Hz, 1H), 3.30 - 3.20 (m, 1H), 1.88 (s, 3H), 1.70 (pd, J = 7.8, 6.9, 3.2 Hz, 2H) , 1.46 - 1.31 (m, 4H), 0.99 - 0.85 (m, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.76, -126.95 - -128.53 (m), -142.19 (ddd, J = 21.6, 11.0, 7.0 Hz).

Example 13

(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (13b) synthesis of. To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (100 mg, 0.49 mmol) and 10a (77 mg, 0.49 mmol) in THF (3 mL) N,N-diisopropylethylamine (0.340 mL, 1.951 mmol) was added. After stirring at 80° C. for 18 h, 2,4-dimethoxybenzylamine (0.293 mL, 1.951 mmol) was added followed by N,N-diisopropylethylamine (0.255 mL, 1.45 mmol). The reaction was heated in a microwave reactor at 155° C. for 2 h, diluted with EtOAc (60 mL) and washed with water (60 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting in hexanes-EtOAc followed by EtOAc-MeOH to give 13b as a mixture of isomers. LC/MS (ESI) calculated for _{C 23} H ₃₁ N ₅ O ₃ S: m/z 458.22, found 458.30 [M+H] ⁺ ; t _R = 0.93 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 7.56 - 7.49 (m, 1H), 7.25 - 7.21 (m, 1H), 7.09 (dd, J = 5.4, 2.5 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 4.67 - 4.46 (m, 2H), 4.45 - 4.29 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H) ), 3.75 - 3.63 (m, 1H), 3.46 - 3.34 (m, 1H), 1.80 (s, 3H), 1.65 - 1.43 (m, 2H), 1.40 - 1.29 (m, 4H), 0.94 - 0.84 (m) , 3H).

Synthesis of (R)-N-(2-((2-aminothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (13). To 13b (46.4 mg, 0.10 mmol) was added TFA (3 mL). After 90 min, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 20% aq. acetonitrile - 40% aq. acetonitrile, gradient over 10 min) to give 13 as its TFA salt. LC/MS (ESI) calculated for _{C 14} H ₂₁ N ₅ OS: m/z 308.15, found 308.20 [M+H] ⁺ ; t _R =0.65 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.07 (d, J = 5.4 Hz, 1H), 7.17 (d, J = 5.4 Hz, 1H), 4.17 (ddt, J = 9.5, 7.7, 4.7 Hz, 1H), 3.79 (dd, J = 13.5, 4.8 Hz, 1H), 3.50 (dd, J = 13.5, 7.7 Hz, 1H), 1.91 (s, 3H), 1.60 (ddd, J = 13.8, 9.3, 4.5 Hz) , 1H), 1.53 - 1.44 (m, 1H), 1.44 - 1.27 (m, 5H), 0.92 (t, J = 6.9 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol- d ₄ ) δ -77.89.

Example 14

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pteridin-4-yl)amino)-2-methylhexyl)acetamide (14b). In a solution of 1i (100 mg, 0.58 mmol) and 2,4-dichloropteridine (96 mg, 0.58 mmol, supplied by Astattech, Inc.) in THF (2.5 mL) N,N-diisopropyl Ethylamine (0.25 mL, 1.9 mmol) was added. The mixture was heated in a microwave reactor at 100° C. for 30 minutes. To this mixture was then added 2,4-dimethoxybenzylamine (0.15 mL, 0.96 mmol) and heated in a microwave reactor at 120° C. for 30 minutes. The reaction was diluted with EtOAc (15 mL), washed with water (15 mL) and brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc followed by EtOAc-MeOH to give 14b. LC/MS (ESI) calculated for _{C 24} H ₃₃ N ₇ O ₃ : m/z 468.26, found 468.35 [M+H] ⁺ ; t _R = 0.96 min, on LC/MS Method A.

¹ H NMR (400 MHz, chloroform- d ) δ 8.75 - 8.25 (m, 1H), 8.10 (d, J = 14.5 Hz, 1H), 7.24 (dd, J = 83.8, 8.2 Hz, 1H), 7.08 - 6.86 (m, 1H), 6.52 - 6.29 (m, 2H), 4.63 (d, J = 26.6 Hz, 2H), 3.83 (s, 3H), 3.77 (d, J = 8.0 Hz, 3H), 3.74 - 3.64 ( m, 2H), 1.95 (d, J = 24.8 Hz, 3H), 1.63 (t, J = 12.8 Hz, 1H), 1.39 (s, 3H), 1.34 - 1.16 (m, 5H), 0.90 - 0.81 (m , 3H).

Synthesis of (R)-N-(2-((2-aminopteridin-4-yl)amino)-2-methylhexyl)acetamide (14). To 14b (52.2 mg, 0.11 mmol) was added TFA (3 mL). After 5 h, the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3 x 20 mL). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give it as its TFA salt. LC/MS (ESI) calculated for _{C 15} H ₂₃ N ₇ O: m/z 318.20, found 318.45 [M+H] ⁺ ; t _R =0.67 min, on LC/MS method A.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.77 (d, J = 2.4 Hz, 2H), 8.65 (d, J = 2.3 Hz, 1H), 3.93 (d, J = 14.1 Hz, 1H), 3.52 (d, J = 14.1 Hz, 1H), 2.25 - 2.12 (m, 1H), 1.96 (s, 4H), 1.56 (s, 3H), 1.36 (td, J = 8.4, 6.9, 4.8 Hz, 4H), 0.96 - 0.87 (m, 3H).

HPLC method

Method for LC/MS HPLC (Method A): HPLC LC/MS chromatograms are Kinetex 2.6 using 1.85 min gradient elution from 2% aqueous acetonitrile with 0.1% formic acid modifier - 98% aqueous acetonitrile u C18 100 A, Thermo Scientific LCQ LC/MS system elution eluting with a 5x30 mm HPLC column.

Method for LC/MS HPLC (Method B): HPLC LC/MS chromatograms are Kinetex 2.6u C18 100 using 2.85 min gradient elution from 2% aqueous acetonitrile with 0.1% formic acid modifier - 98% aqueous acetonitrile A, generated using a Thermo Scientific LCQ LC/MS system eluting with a 5x30 mm HPLC column.

Cells and reagents

Cryopreserved human PBMCs isolated from healthy donors were purchased from StemCell Technologies (Vancouver, Canada). The cell culture medium used was RPMI (L-glutamine) supplemented with 10% fetal bovine serum (Hyclone, GE Healthcare, Logan, Utah) and penicillin-streptomycin (Mediatech). Mediatheque, Manasas, Virginia). Human TNFα, IL12p40, and IFNα2a 384-well assay capture plates, standards, buffers and processing reagents were obtained from MesoScale Discovery Technologies (MSD; Rockville, MD).

Lyophilized human PBMCs (1×10e8 cells/ml) were thawed at 37° C. and resuspended in 25 mL warm cell culture medium. Cells were pelleted at 200Xg (Beckman Avanti JE) for 5 minutes and resuspended in 20 mL of fresh culture medium. Cells were counted using a Cellometer (Nexcelcom Bioscience), adjusted to 2x10e6 cells, and incubated for 2 hours in an incubator set _{at 37° C., 5% CO 2 for cryopreservation.} recovered from Compounds were serially diluted in half-log steps in DMSO to create a 10-point dose range. Using a Bravo pipette (Agilent) equipped with a 384 well head, pour 0.4 μL of compound into a 384 well black, clear bottom plate (Greiner Bio-One) containing 30 μL of cell culture medium. One), Germany) were transferred to each well. Recovered PBMCs were then dispensed into assay plates at 50 μL per well (100k cells/well) using a microflow multichannel dispenser (Biotek). The final DMSO concentration was 0.5%. DMSO was used as a negative control. Plates were incubated at 37° C. for 24 hours. PBMCs in assay plates were pelleted by 5 min centrifugation at 200Xg (Beckman Avanti JE).

Using a Biomek FX 384 well pipetting station (Beckman), conditioned culture medium (CCM) from the assay plate was transferred to an MSD capture plate customized for each cytokine. For IFNα and IL12-p40 detection, 25 μL and 20 μL of CCM were added directly to each capture plate, respectively. For TNFα detection, CCM was diluted 1:9 in fresh culture medium and 20 μL of diluted CCM was used. A standard curve was generated using serially diluted calibration standards for each cytokine and the assay linearity was established. The plates were sealed and incubated overnight at 4° C. in a plate shaker (Titer Plate) set at 200 rpm. The next day, antibodies specific for each cytokine were diluted 1:50 in MSD Diluent 100 Antibody Dilution Buffer. Diluted antibody was added at 10 μL/well to the corresponding capture plate and incubated for 1-2 h at RT on a shaker. Plates were washed with PBST buffer (3X, 60 μl/well) using a Biotech Multiflow Plate Washer. MSD read buffer diluted 2X in deionized water was added via Biomek FX instrument at 35 μL/well. The plate was read immediately in the MSD6000 reader. Data in each assay plate were normalized to positive and negative controls. AC ₅₀ values represent compound concentrations at half-maximal effect, based on normalized percent activation and calculated by non-linear regression using pipeline pilot software (Accelrys, San Diego, CA) .

The results of the cytokine profiling assay are reported in Table 1 below.

This disclosure provides references to various embodiments and techniques. However, it should be understood that many changes and modifications may be made while remaining within the spirit and scope of the present disclosure.

Claims (50)

A compound of formula (I): or a pharmaceutically acceptable salt thereof.

here,
R ¹ is —H, C _1-4 alkyl, or C _1-4 haloalkyl;
R ² is C _1-6 alkyl or C _1-6 haloalkyl;
Q is CR ⁴ ;
R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein
C _5-6 cycloalkyl and phenyl are each independently optionally substituted ^{with 1 to 3 R 5 ;}
each R ⁵ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with ^{1-3 R Z} , C _1-4 haloalkyl, C _1-4 alkoxy, —C (O)OH, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), - C(O)N(C _1-4 alkyl) ₂ , —N(H)C(O)C _1-4 alkyl, —S(O) ₂ C _1-4 alkyl, or optionally with ^{1-3 R Z} 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from substituted oxygen, nitrogen, and sulfur;
5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;}
each R ⁶ is independently halogen, —OH, —NH ₂ , —CN, _{C 1-4} alkyl optionally substituted with 1 phenyl optionally substituted with ^{1-3 R Z ;} C _1-4 haloalkyl, C _1-4 alkoxy, —S(O) ₂ C _1-4 alkyl; 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;} phenyl optionally substituted with 1 to 3 R ^{Z ;} or 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}
5-6 membered heterocyclyl is optionally substituted with ^{1-3 R 7 ;}
R ⁷ is halogen, —OH, C _1-4 alkyl, C _1-4 alkoxy, or —C(O)R ⁸ ;
each R ⁸ _{is independently C 1-4} alkyl optionally substituted with —CN or —NH _{2 ;} C _1-4 haloalkyl; C _5-6 cycloalkyl, 5-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with ^{1-3 R Z ;} or 5-10 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R ^{Z ;}
each R ^Z is independently —NH ₂ , C _1-4 alkyl, halogen, —CN, —OC _1-4 alkyl, C _1-4 haloalkyl, or —C(O)NH ₂ ;
with the proviso that formula I is

this is not The compound of claim 1 , wherein R ¹ is —H or C _1-4 alkyl. 3. A compound according to claim 1 or 2, wherein R ¹ is methyl. 3. A compound according to claim 1 or 2, wherein R ² is C _3-6 alkyl. ^{3. A} compound according to claim 1 or 2, wherein R 3 and R ⁴ together form a 6-membered cycloalkyl. 3. A compound according to claim 1 or 2, wherein R ³ and R ⁴ _{together are C 1-2} alkyl optionally substituted with 1 to 3 chloro, fluoro, bromo, —CN, —OH, C _1-2 alkoxy; -C(O)C _1-2 alkyl, -C(O)OC _1-2 alkyl, pyrazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} or phenyl optionally substituted with imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl.} ^{3. A} compound according to claim 1 or 2, wherein R 3 and R ⁴ together form pyrazinyl, pyridinyl or thienyl optionally substituted with 1 to 3 C _{1-2 alkyl.} ^{3 .} The method of claim 1 , wherein R 3 and R ⁴ together form tetrahydropyridinyl optionally substituted with —C(O)R ^{8 , wherein R 8} is optionally substituted with —CN or —NH _{2 .} C _1-4 alkyl, C _1-3 haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionally substituted with _{1 to 3 C 1-3 alkyl;} thiazolyl, imidazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} oxazolyl, isoxazolyl optionally substituted with 1 to 3 C _{1-2 alkyl;} A compound that is thiadiazolyl, phenyl, pyrazinyl, or quinolinyl. 3. The method of claim 1 or 2,
R ¹ is —H or C _1-4 alkyl;
R ² is C _3-6 alkyl;
R ³ and R ⁴ together are C _5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein
phenyl is optionally substituted with 1 to 3 halogens;
5-6 membered heteroaryl is optionally substituted with ^{1-3 R 6 ;}
each R ⁶ is independently halogen, —OH, C _1-4 alkyl, or C _1-4 alkoxy;
5-6 membered heterocyclyl is optionally substituted with 1 to 3 -C(O)C _{1-4 alkyl}
compound. 3. The compound according to claim 1 or 2, wherein formula (I) is represented by formula (II):

3. The compound according to claim 1 or 2, wherein formula (I) is represented by formula (III):

^3. The method of claim 1 or 2, wherein R 3 and R ⁴ together are

wherein R ⁵ is optionally present. 10. The compound of claim 9, wherein R ³ and R ⁴ together form tetrahydropyridinyl optionally substituted with 1 to 3 C(O)C _{1-2 alkyl.} 10. The compound of claim 9, wherein R ³ and R ⁴ together form a phenyl optionally substituted with 1 to 3 fluoro. 10. The compound of claim 9, wherein R ³ and R ⁴ together form pyrazinyl, thienyl or pyridinyl. ^3. The method of claim 1 or 2, wherein R 3 and R ⁴ together are

wherein each of R ⁵ , R ⁶ , and R ⁷ is optionally present. 3. A compound according to claim 1 or 2 selected from:

, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing a viral infection comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 19. The pharmaceutical composition of claim 18, further comprising one or more additional therapeutic agents. 20. The method of claim 19, wherein the at least one additional therapeutic agent is a HBV DNA polymerase inhibitor, a Toll-like receptor 7 modulator, a Toll-like receptor 8 modulator, a Toll-like receptor 7 and 8 modulator, a Toll-like receptor 3 modulator, an interferon. Alpha ligand, HBsAg inhibitor, HbcAg targeting compound, cyclophilin inhibitor, HBV therapeutic vaccine, HBV prophylactic vaccine, HBV virus entry inhibitor, NTCP inhibitor, viral mRNA targeting antisense oligonucleotide, short interfering RNA (siRNA), hepatitis B virus E antigen Inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigen of hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), retinoic acid-inducible gene 1 A pharmaceutical composition selected from the group consisting of stimulators, stimulators of NOD2, recombinant thymosin alpha-1 and hepatitis B virus replication inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, and combinations thereof. 20. The method of claim 19, wherein the one or more additional therapeutic agents is entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir A pharmaceutical composition selected from the group consisting of alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine. 20. The method of claim 19, wherein the at least one additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, HIV integrase A pharmaceutical composition selected from an inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof. A pharmaceutical composition for modulating TLR8 for treating or preventing viral infection, hepatitis B virus infection, HIV infection or hyperproliferative disease, comprising a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing a viral infection, a hepatitis B virus infection, an HIV infection or a hyperproliferative disease, comprising a therapeutically effective amount of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof. 24. The pharmaceutical composition of claim 23, further comprising one or more additional therapeutic agents. A pharmaceutical composition for treating or preventing a viral infection comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing hepatitis B virus infection, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 28. The pharmaceutical composition of claim 27, further comprising one or more additional therapeutic agents. 28. The method of claim 27, wherein the HBV DNA polymerase inhibitor, Toll-like receptor 7 modulator, Toll-like receptor 8 modulator, Toll-like receptor 7 and 8 modulator, Toll-like receptor 3 modulator, interferon alpha ligand, HBsAg inhibitor, HbcAg Targeting compound, cyclophilin inhibitor, HBV therapeutic vaccine, HBV prophylactic vaccine, HBV virus entry inhibitor, NTCP inhibitor, viral mRNA targeting antisense oligonucleotide, short interfering RNA (siRNA), hepatitis B virus E antigen inhibitor, HBx inhibitor, cccDNA inhibitor , HBV antibody including HBV antibody targeting the surface antigen of hepatitis B virus, thymosin agonist, cytokine, nucleoprotein inhibitor (HBV core or capsid protein inhibitor), retinoic acid-inducible gene 1 stimulator, NOD2 stimulator, recombinant 1, 2, 3 or 4 additional therapeutic agents selected from the group consisting of thymosin alpha-1 and hepatitis B virus replication inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, and combinations thereof A pharmaceutical composition comprising 28. The method of claim 27, wherein adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disop Loxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®) or lamivudine (efivir- A pharmaceutical composition comprising 1, 2, 3 or 4 additional therapeutic agents selected from HBV (EPIVIR-HBV)®). A pharmaceutical composition for treating or preventing HIV infection comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 32. The pharmaceutical composition of claim 31 comprising one or more additional therapeutic agents. 32. The method of claim 31, wherein the HIV protease inhibitory compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, gp41 A pharmaceutical comprising 1, 2, 3 or 4 additional therapeutic agents selected from the group consisting of inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating or preventing HIV, and combinations thereof. composition. 32. The method of claim 31, wherein Triumeq® (dolutegravir+abacavir+lamivudine), dolutegravir+abacavir sulfate+lamivudine, raltegravir, Truvada® (Te nofovir disoproxil fumarate + emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate + lamivudine, ABC+3TC), Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild® (elvitegravir+cobicistat+te Nofovir disoproxil fumarate + emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine + tenofovir disoproxil fumarate +M) Tricitabine), cobicistat, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvi Tegravir, Aluvia® (Kaletra®, lopinavir + ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir, darunavir, ramivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, dida Nosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir , delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir D Soproxil fumarate, phosphazide, lamivudine + nevirapine + zidovudine, (2R,5S,13aR)- N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methano pyrido [1 ', 2': 4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide, (2S, 5R, 13aS) -N- (2,4 -difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1', 2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl) -7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1', 2'-d]pyrazine-9-carboxamide, (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1, 2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide, (2R ,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octa Hydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, and (1R,4S, 12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4 -methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir A pharmaceutical composition comprising one, two, three or four additional therapeutic agents selected from disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate. A pharmaceutical composition for treating a hyperproliferative disease comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 36. The pharmaceutical composition of claim 35, further comprising one or more additional therapeutic agents. 36. The pharmaceutical composition of claim 35, wherein the hyperproliferative disease is cancer. 38. The pharmaceutical composition of claim 37, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, or recurrent or metastatic squamous cell carcinoma. A kit for treating a viral infection, a hepatitis B virus infection, an HIV infection or a hyperproliferative disease, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof. An article of manufacture for the treatment of viral infection, hepatitis B virus infection, HIV infection or hyperproliferative disease, comprising a unit dose of a compound of claim 1 . A pharmaceutical composition for use in modulating toll-like receptors in vitro to treat a viral infection, a hepatitis B virus infection, an HIV infection or a hyperproliferative disease, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof . delete delete delete delete delete delete delete delete delete